Human tlr8-selective agonists

ABSTRACT

The disclosure provides human toll-like receptor modulators of general Formula (II), wherein R1, R2, R3, R4, R5, R6, R7, R8 are defined herein.

FIELD OF THE INVENTION

Embodiments of the invention are directed to compounds which areToll-Like Receptor (TLR)-8 agonists. In particular, the compounds areTLR8-specific agonists which modulate immune responses or can be used asadjuvants.

BACKGROUND

The Centers for Disease Control and Prevention (CDC) has declaredvaccination and the control of infectious diseases to be among thegreatest public health achievements of the 20th century. Vaccines affordprotection by the induction of immune responses, both humoral andcellular, specifically directed against the pathogen. A significanttrend in contemporary vaccinology is the design of highly effectivesubunit vaccines, and the majority of modern subunit vaccines whichutilize highly purified, recombinantly-expressed protein immunogens arereliant on vaccine adjuvants to provide the initial, innateimmune-activating signals which determine the specificity, magnitude,quality, and durability of downstream adaptive immune responses.

With few exceptions, the majority of currently available vaccinescontain a single adjuvant—‘alum’ introduced by Alexander Glenny in 1926(Glenny, A. T.; et al., J. Path. Bact. 1926, 29, 38-45). ‘Alum’ (amixture of aluminum phosphate and aluminum hydroxide), appears topromote a T helper 2 (Th2)-skewed antibody response, and is virtuallyineffective at inducing cytotoxic T lymphocyte or mucosal IgA antibodyresponses (Gupta, R. K.; Siber, G. R. Vaccine 1995, 13, 1263-1276;Gupta, R. K. Adv. Drug Deliv. Rev. 1998, 32, 155-172). Indeed,alum-adjuvanted pertussis subunit vaccines (Klein, N. P. Hum. Vaccin.Immunother. 2014, 10, 2684-2690), which supplanted killed whole-cellpertussis vaccines in the 1990s, induce immunity that rapidly wanes(Sheridan, S. L. et al. Exp. Rev. Vaccines 2014, 13, 1081-1106; Lavine,J. S. et al. Vaccine 2012, 30, 544-51; Suryadevara, M. et al. Hum.Vaccin. Immunother. 2015, 11, 1744-1747); the short-lived immunity isthought to contribute to the recent re-emergence of pertussis in theUnited States (Clark, T. A. J. Infect. Dis. 2014, 209, 978-981; Cherry,J. D. New Eng. J. Med. 2012, 367, 785-787) and elsewhere in the world(Zepp, F. et al. Lancet Infect. Dis. 2011, 11, 557-570; Hara, M. et al.BMC Infect. Dis. 2015, 15, 45). In experimental models of pertussis,alum-adjuvanted acellular pertussis vaccines protected baboons in theshort term from severe pertussis-like symptoms, but failed to preventcolonization of B. pertussis, allowing transmission of the pathogen tounvaccinated animals (Warfel, J. M. Proc. Natl. Acad. Sci USA 2014, 111,787-792); killed whole-cell pertussis vaccines, on the other hand,elicited strong B. pertussis-specific Th17 and Th1 memory, indicatingthat both durability and quality of immune responses are pivotal in theinduction and maintenance of long-term sterilizing immunity.

Innate immune signals evoked by vaccine adjuvants include thoseoriginating from Toll-like receptors (TLRs) (Hoffmann, J. et al. Curr.Opin. Immunol. 2013, 25, 1-3; Kumagai, Y. et al. J. Allergy Clin.Immunol. 2010, 125, 985-992; Kawai, T. et al. Nat. Immunol. 2010, 11,373-384), as well as RIG-I-like receptors (Loo, Y. M. et al. Immunity.2011, 34, 680-692) and NOD-like receptors (NLRs) (Kersse, K. et al.Cytokine Growth Factor Rev. 2011, 22, 257-276; Clarke, T. B. et al.Immunol. Rev. 2011, 243, 9-25). There are 10 functional TLRs encoded inthe human genome, which are trans-membrane proteins with anextracellular domain having leucine-rich repeats (LRR) and a cytosolicdomain called the Toll/IL-1 receptor (TIR) domain. The ligands for thesereceptors are highly conserved molecules such as lipopolysaccharides(LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), doublestranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), andprofilin present on uropathogenic bacteria (TLR11). TLR1, -2, -4, -5,and -6 recognize extracellular stimuli, while TLR3, -7, -8 and -9function within the endolysosomal compartment.

The current understanding of how the engagement of innate immunereceptors by vaccine adjuvants leads to the deployment and amplificationof immunogen-specific adaptive immune responses (Hoffmann, J. et al.Curr. Opin. Immunol. 2013, 25, 1-3; Kumagai, Y. et al. J. Allergy Clin.Immunol. 2010, 125, 985-992; Cottalorda, A. et al. Eur. J Immunol. 2006,36, 1684-1693), and the maintenance of immunological memory isincomplete, and may involve multiple mechanisms and pathways; these mayinclude (i) enhanced antigen uptake and presentation by professionalantigen presenting cells (APCs) (Xu, W. et al. Front. Immunol. 2014, 4,504; Platt, A. M. et al. Adv. Immunol. 2013, 120, 51-68; Teijeira, A. etal. Front. Immunol. 2013, 4, 433; Teijeira, A.; et al. Semin.Immunopathol. 2014, 36, 261-274), (ii) amplification of cross-talk(Jenkins, M. K. et al. Annu. Rev. Immunol. 2001, 19, 23-45; Garside, P.et al. Science 1998, 281, 96-99; Miga, A. J. et al. Eur. J. Immunol.2001, 31, 959-965) between naïve B lymphocytes recognizing theimmunogen, and rare naïve CD4+ T cells expressing T cell antigenreceptors (TCRs) specific for antigen-derived peptide/majorhistocompatibility complex class II molecules (MHCII) displayed by suchnaïve B cells, (iii) accelerated differentiation of CD4+ T cells intofollicular helper T cells (Tfh) (Breitfeld, D. et al. J. Exp. Med. 2000,192, 1545-1552; Hale, J. S. et al. Front. Immunol. 2015, 6, 16; Crotty,S. Nat. Rev. Immunol. 2015, 15, 185-189; Crotty, S. Annu. Rev. Immunol.2011, 29, 621-663), and, (iv) subsequent B lymphocyte differentiationevents leading to immunoglobulin affinity maturation (McHeyzer-Williams,L. J. et al. Curr. Opin. Immunol. 2009, 21, 266-273; Nurieva, R. I. etal. Cell. Molec. Immunol. 2010, 7, 190-19), and the generation ofantigen-specific memory B cells and plasma cells (Hauser, A. E. et al.Ann. NY Acad. Sci. 2003, 987, 266-269; Borghesi, L. et al. Immunol. Res.2006, 36, 27-32; Johnson, K. et al. Molec. Immunol. 2005, 42, 749-761).

The need for the development of safe and effective vaccine adjuvants hasfueled the exploration of a variety of innate immune stimuli, whichinclude agonists of TLR2 (Salunke, D. B. et al. J. Med. Chem. 2012, 55,3353-3363; Salunke, D. B. et al. J. Med Chem. 2013, 56, 5885-5900; Wu,W. et al. J Med. Chem. 2010, 53, 3198-3213), TLR7 (Shukla, N. M. et al.Bioorg. Med. Chem. Lett. 2009, 19, 2211-2214; Shukla, N. M. et al. J.Med. Chem. 2010, 53, 4450-4465; Shukla, N. M. et al. Bioorg. Med. Chem.Lett. 2010, 20, 6384-6386; Shukla, N. M. et al. Bioorg. Med. Chem. Lett.2011, 21, 3232-3236; Shukla, N. M. et al. Med. Chem. 2011, 19,3801-3811; Shukla, N. M. et al. J Med Chem. 2012, 55, 1106-1116; Shukla,N. M. et al. PLoS ONE. 2012, 7, e43612; Yoo, E. et al. Org. Biomol.Chem. 2013, 11, 6526-6545; Yoo, E. et al. J. Med. Chem. 2014, 57,7955-7970), TLR8 (Salunke, D. B et al. J. Med. Chem. 2012, 55,8137-8151; Kokatla, H. P. et al. Org. Biomol. Chem. 2013, 11, 1179-1198;Kokatla, H. P. et al. J. Med. Chem. 2013, 56, 6871-6885; Kokatla, H. P.et al. Chem. Med. Chem. 2014, 9, 719-723; Beesu, M. et al. J. Med. Chem.2014, 57, 7325-7341), nucleotide oligomerization domain 1 (NOD1)(Agnihotri, G. et al J. Med. Chem. 2011, 54, 1490-1510.), as well as C—Cchemokine receptor type 1 (CCR1) (Ukani, R. et al. Bioorg. Med. Chem.Lett. 2012, 22, 293-295). Structure-activity relationship studies haveproven useful in providing tools with which to examine how thesedifferent classes of innate immune signaling molecules affect andmodulate pathways linking the innate and adaptive immune systemsdescribed above.

SUMMARY

The present disclosure provides a compound represented by Formula (II):

or a salt thereof, wherein:

R¹, R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of: H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R⁵⁰,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, optionally substituted C₃₋₂₀carbocycle, and optionally substituted 3- to 20-membered heterocycle,wherein at least one of R¹ and R³ is selected from the group consistingof —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl,optionally substituted C₃₋₂₀ carbocycle, and optionally substituted 3-to 20-membered heterocycle;

R⁶ is selected from the group consisting of —OR¹¹, —N(R¹¹)₂, —SR¹¹,optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R⁷ and R⁸ are independently selected from H, optionally substitutedC₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, optionallysubstituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle andoptionally substituted 3- to 12-membered heterocycle; R¹⁰ isindependently selected at each occurrence from the group consisting ofH, optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀ alkynyl, optionally substitutedC₃₋₁₂ carbocycle and optionally substituted 3- to 12-memberedheterocycle; and

R¹¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

In certain embodiments, at least one of R¹ and R³ is selected from thegroup consisting of —OR¹⁰, —N(R¹⁰)₂, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰,—C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀alkynyl. In some embodiments, at least one of R¹ and R³ is selected fromthe group consisting of optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl.

In some embodiments, R¹ is optionally substituted C₁₋₁₀ alkyl. In someembodiments, R¹ is optionally substituted C₁₋₅ alkyl. In someembodiments, R¹ is selected from the group consisting of: optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and optionally substituted C₃₋₂₀ carbocycle andoptionally substituted 3- to 20-membered heterocycle, wherein the C₃₋₂₀carbocycle and 3- to 20-membered heterocycle optional substituents areone or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl. In some embodiments, R¹ is substituted with —N(R⁵⁰)₂.In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from H, halogen, and —CN. In someembodiments, R¹ is hydrogen. In some embodiments, R¹ is C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₃₋₂₀ carbocycle or 3- to 20-memberedheterocycle any of which is substituted with N(R⁵⁰)₂ and R³ is selectedfrom H, halogen, and —CN, such as R³ is hydrogen.In some embodiments, R³ is optionally substituted C₁₋₁₀ alkyl. In someembodiments, R³ is optionally substituted C₁₋₅ alkyl. In someembodiments, R³ is selected from the group consisting of: optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R¹⁰)₂; and optionally substituted C₃₋₂₀ carbocycle andoptionally substituted 3- to 20-membered heterocycle, wherein the C₃₋₂₀carbocycle and 3- to 20-membered heterocycle optional substituents areone or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl. In some embodiments, R³ is substituted with —N(R⁵⁰)₂.In some embodiments, R³ is selected from:

In some embodiments, R³ is selected from H, halogen, and —CN. In someembodiments, R³ is hydrogen. In some embodiments, R³ is C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₃₋₂₀ carbocycle or 3- to 20-memberedheterocycle any of which is substituted with —N(R⁵⁰)₂ and R¹ is selectedfrom H, halogen, and —CN, such as R¹ is hydrogen.In some embodiments, R², R⁴, and R⁵ are independently selected from thegroup consisting of: H,halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰, —C(O)R¹⁰,—C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, and optionallysubstituted C₁₋₂₀ alkyl. In some embodiments, R², R⁴, and R⁵ areindependently selected from the group consisting of: H, halogen, —OR¹⁰,—N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, and optionally substituted C₁₋₂₀ alkyl. Insome embodiments, R², R⁴, and R⁵ are independently selected from thegroup consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-membered heterocycleoptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

In some embodiments, R² is hydrogen. In some embodiments, R⁴ ishydrogen. In some embodiments, R⁵ is hydrogen.

In some embodiments, R¹⁰ is selected from the group consisting of:optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andwherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

In some embodiments, R⁶ is selected from the group consisting ofoptionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl. In some embodiments,R⁶ is selected from the group consisting of optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀ alkenyl, and optionally substitutedC₁₋₂₀ alkynyl. In some embodiments, R⁶ is selected from the groupconsisting of optionally substituted C₁₋₁₀ alkyl. In some embodiments,R⁶ is selected from the group consisting of: optionally substitutedC₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl, optionallysubstituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, andC₂₋₂₀ alkynyl optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰,—C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰, C₃₋₁₂ carbocycle, and3- to 12-membered heterocycle, wherein the C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andoptionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl. In some embodiments, R⁶ is:

In some embodiments, R⁷ and R⁸ are independently selected from H andoptionally substituted C₁₋₁₀ alkyl. In some embodiments, R⁷ and R⁸ areeach H. In some embodiments, R⁷ and R⁸ are independently selected fromthe group consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andwherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl. In someembodiments, a compound of the present disclosure is represented by theFormula:

or a salt of any one thereof. In some embodiments, a compound of thepresent disclosure is represented by the Formula:

or a salt of any one thereof.In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound or salt disclosed herein andpharmaceutically acceptable excipient. In some embodiments, thecomposition further comprises a vaccine.

In some aspects, the present disclosure provides a method for modulatingactivity of a human toll-like receptor, comprising administering to asubject in need thereof, a compound of formula (III):

or a salt thereof, wherein:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H,

halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰, —C(O)R²⁰,—C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionally substitutedC₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, andoptionally substituted 3- to 20-membered heterocycle,

wherein at least one of R¹¹, R¹², R¹³, and R¹⁴ is selected from thegroup consisting of —OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionally substituted C₃₋₂₀carbocycle, optionally substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, and optionallysubstituted 3- to 20-membered heterocycle;

R¹⁶ is optionally substituted C₁₋₂₀ alkyl, —OR²¹, —N(R²¹)₂, —SR²¹,optionally substituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀alkynyl;

R¹⁷ and R¹⁸ are independently selected from H, optionally substitutedC₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, optionallysubstituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle andoptionally substituted 3- to 12-membered heterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₁₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

In some embodiments, a method of the current disclosure comprisesmodulating the activity of the human toll-like receptor, comprisingagonizing the human toll-like receptor. In some embodiments, a humantoll-like receptor comprises hTLR8. In some embodiments, a methodfurther comprises administering a vaccine to the subject before, inconjunction with, or after administration of the compound or salt.

In some aspects, the present disclosure provides a method of increasingan immune response to an antigen or vaccine, wherein the methodcomprises administering to a subject in need thereof a compound ofFormula (III):

or a salt thereof, wherein:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H,

halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰, —C(O)R²¹,—C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionally substitutedC₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, andoptionally substituted 3- to 20-membered heterocycle, wherein at leastone of R¹¹, R¹², R¹³, and R¹⁴ is selected from the group consisting of—OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰,—S(O)₂OR²⁰, optionally substituted C₃₋₂₀ carbocycle, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, and optionally substituted 3- to20-membered heterocycle;

R¹⁶ is selected from the group consisting of optionally substitutedC₁₋₂₀ alkyl, —OR²¹, —N(R²⁰)₂, —SR²¹, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R¹⁷ and R¹⁸ are independently selected from the group consisting of H,optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₀alkenyl,optionally substituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂carbocycle and optionally substituted 3- to 12-membered heterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₁₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

Embodiments of the invention are directed to compounds, formulations andpharmaceutical compositions comprising one or more compounds having ageneral structural Formula I:

wherein: R₁, R₅ are independently: H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂, C_((m+1))H_((2m+1)),C_((m+1))H_((2m+1))NH₂, C_((m+1))H_((2m+1))CONH₂, C_((m+1))H_((2m+1)),CR′NH₂, C_((m+1))H_((2m+1))—C₄₋₂₀ aryl-C_((m+1))H_((2m+1))—NH₂,C_(m)H_(2m+2), C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₁₋₂₀ alkylamino, C₂₋₂₀ alkenyl,C₂₋₂₀ alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkylheterocycle, C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, where m is aninteger from 0 to 10, and b is an integer from 0 to 10;the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₄₋₂₀heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle, C₇₋₂₀ alkylheteroaryl, C₁₋₂₀ alkyoxyl is unsubstituted or optionally substitutedwith a functional group comprising H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, or an amino acid side chainor peptide fragment, the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle,C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, and the C₁₋₆ alkyl is optionallyinterrupted by one or more O, S, or N atoms, or one or more groupscomprising cycloalkyl, C_((m+1))H_((2m+1)), C_((m+1))H_((2m+1))NH₂,CH—C(O)—O—, —O—C(O)—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and—O—C(O)—NH—, R′ is H, OH, halogen, NO₂, —NH₂, CN, —COOH, heteroarylhaving 1 to 4 N, O and/or S atoms, C₄₋₂₀ aryl, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀ heterocycle or C₄₋₁₀ heteroaryl; thegroups R₂, R₃, and R₄ are independently: H, —OH, —NH₂, —CH₂, —COOH,—OR′, —NH₂, —NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂where m is an integer from 0 to 10, and b is an integer from 0 to 10,C₁₋₅₀ alkyl, the C₁₋₅₀ alkyl is unsubstituted or optionally substitutedwith a functional group comprising one or more of: H, —OH, —OR′, —NH₂,—NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, an amino acidside chain or peptide fragment, where R¹ is selected from radicalsconsisting of H, heteroaryl having 1 to 4 N, O and/or S atoms, C₁₋₂₀alkyl, C₁₋₂₀ alkylamino, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀heterocycle, C₄₋₁₀ heteroaryl, ammonium and salts thereof, sulfates,sulfonates, thiosulfonates, boronates, phosphates, phosphonate,guanidine, amidine, pyridine, pyridium, alkali metal groups, nitrates,chlorates, perchlorates, acetates, chloride, bromide, iodide and saltsthereof, an alkali metal salt of sulfonic acid; an alkali metal salt ofphosphonic acid; a pharmaceutically acceptable salt; a sugar or apolyhydroxy group.

In another embodiment, a pharmaceutical composition comprises one ormore compounds having a general structure of Formula I.

Other aspects are described infra.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows three structures: dual TLR7/8-activeN¹-4-aminomethylbenzyl-substituted imidazoquinoline (1);N¹-3-aminomethylbenzyl-substituted imidazoquinoline (2); andTLR8-agonistic 3-pentylquinolin-2-amine (3). Crystal structures ofcompounds 1 and 2 bound to human TLR8 are also shown. Dashed lines inyellow depict direct hydrogen bonds.

FIG. 2 is a graph showing the agonistic activities of analogues 18a,18b, 34a, and 34b in human TLR8 reporter gene assays. Means±SD onquadruplicates are shown. Also included is 3, used as areference/comparator compound.

FIGS. 3A-3D are graphs showing representative cytokine induction data(excerpted from a 63 cytokine panel) in human PBMCs. Means±SD onquadruplicates are shown.

FIG. 4 is a graph showing the adjuvanticity of TLR8-active compounds.Cohorts of adult female New Zealand White rabbits (n=4) were immunizedintramuscularly in the flank region with (a) 10 μg of CRM197 in 0.2 mLsaline (unadjuvanted control), or (b) 10 μg of CRM197 in 0.2 mL salineplus 100 μg of lead TLR8 agonists (compounds 3, 34b, and a TLR8-specificfuroquinoline agonist (Kokatla, H. P. et al. J. Med. Chem. 2013, 56,6871-6885)). Pre-immune test-bleeds were obtained on Day 0, and animalswere immunized on Days 1, 15 and 28. A final bleed was obtained on Day38. CRM197-specific ELISAs were performed using automated liquidhandling methods and are depicted as log 10 (immune/preimmune) titers.

FIGS. 5A-5D show the results from an eight-color flow cytometry andgating strategy for identification of B, T, NK lymphocytes, monocytesand granulocytes. FIGS. 5E and 5F show upregulation of CD40 and CD80,respectively, in CD14+ monocytes by TLR8-active compounds.

FIGS. 6A and 6B are graphs showing agonistic potencies of compounds 1and 2 in human TLR7 (FIG. 6A) and TLR8 (FIG. 6B) primary screens.

DETAILED DESCRIPTION

Several aspects of the invention are described below with reference toexample applications for illustration. It should be understood thatnumerous specific details, relationships, and methods are set forth toprovide a full understanding of the invention. One having ordinary skillin the relevant art, however, will readily recognize that the inventioncan be practiced without one or more of the specific details or withother methods. The present invention is not limited by the illustratedordering of acts or events, as some acts may occur in different ordersand/or concurrently with other acts or events. Furthermore, not allillustrated acts or events are required to implement a methodology inaccordance with the present invention.

Definitions

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. Furthermore, to the extent that the terms “including”,“includes”, “having”, “has”, “with”, or variants thereof are used ineither the detailed description and/or the claims, such terms areintended to be inclusive in a manner similar to the term “comprising.”

As used herein, the terms “comprising,” “comprise” or “comprised,” andvariations thereof, in reference to defined or described elements of anitem, composition, apparatus, method, process, system, etc. are meant tobe inclusive or open ended, permitting additional elements, therebyindicating that the defined or described item, composition, apparatus,method, process, system, etc. includes those specified elements—or, asappropriate, equivalents thereof—and that other elements can be includedand still fall within the scope/definition of the defined item,composition, apparatus, method, process, system, etc.

As used in this specification and the appended claims, the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, up to 10%, up to 5%, or up to 1% of a given value or range.Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude within 5-fold,and also within 2-fold, of a value. Where particular values aredescribed in the application and claims, unless otherwise stated theterm “about” meaning within an acceptable error range for the particularvalue should be assumed.

The terms, “compound” and “compounds” as used herein refers to acompound encompassed by the generic formulae disclosed herein, anysubgenus of those generic formulae, and any forms of the compounds, e.g.compounds 18a, 18b, etc., within the generic and subgeneric formulae.Unless specified otherwise, the term further includes the racemates andstereoisomers, of the compound or compounds.

The term “lower” as used herein refers to a group having between one andsix carbons.

The term “alkyl” as used herein refers to a saturated straight,branched, or cyclic, primary, secondary, or tertiary hydrocarbon havingfrom one to about fifty carbon atoms, typically C₁ to C₁₀, andspecifically includes, for example, methyl, trifluoromethyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl,cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. An alkyl group as used herein may be substitutedunless otherwise indicated. Alkyl groups can be optionally substitutedwith one or more moieties including, but not limited to: halogens, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl,or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed, hydroxyl, amino, alkylamino, arylamino,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, or as known to those skilled in the art, forexample, as taught in T. W. Greene and P. G. M. Wuts, “Protective Groupsin Organic Synthesis,” 3^(rd) ed., John Wiley & Sons, 1999, herebyincorporated by reference. An alkyl group may contain one or more O, S,S(O), or S(O)₂ moieties. Examples of “alkyl” as used herein include, butare not limited to, methyl, ethyl, propyl, decyl, undecyl, octadecyl,nonadecyl, eicosyl, heneicosyl, decosyl, tricosyl, tetracosyl, andpentacosyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and thelike. In some embodiments the alkyl comprises 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 carbon atoms.

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with achemical moiety, such as alkyl, alkenyl, or alkynyl is meant to includegroups that contain from x to y carbons in the chain. For example, theterm “C_(x-y) alkyl” refers to substituted or unsubstituted saturatedhydrocarbon groups, including straight-chain alkyl and branched-chainalkyl groups that contain from x to y carbons in the chain. The terms“C_(x-y)alkenyl” and “C_(x-y) alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively. The term “C_(x-y)carbocycle” refers to substituted or unsubstituted carbocycle thatcontains from x to y carbons in the ring.

The term “x- to y-membered” refers to the number of atoms in a chemicalmoiety. For example a 3- to 20-membered heterocycle is a heterocyclethat contains from 3 to 20 ring atoms.

As used herein, “cycloalkyl” refers to a cyclic saturated hydrocarbongroup having from about three to about fifty carbon atoms, optionallysubstituted with substituents, for example: halogens, halides,alkylhalides, selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. “Cycloalkyl” includes,by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl, and the like.

The term “carbocycle” as used herein refers to a saturated, unsaturatedor aromatic ring in which each atom of the ring is carbon. Carbocycleincludes, for example, 3- to 10-membered monocyclic rings, 6- to12-membered bicyclic rings, and 6- to 12-membered bridged rings. Eachring of a polycyclic carbocycle may be selected from saturated,unsaturated, and aromatic rings. In an exemplary embodiment, an aromaticring, e.g., phenyl, may be fused to a saturated or unsaturated ring,e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination ofsaturated, unsaturated and aromatic bicyclic rings, as valence permits,are included in the definition of carbocycle. Exemplary carbocyclesinclude cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl,indanyl, and naphthyl. A carbocycle may be optionally substituted withone or more substituents as described herein.

The terms “heterocycle” and “heterocyclic” as used herein are usedinterchangeably to refer to a three to about twelve-memberedheterocyclic ring optionally aromatic or possessing one or more degreesof unsaturation, containing one or more heteroatomic substitutions, forexample: —S—, —SO—, —SO₂—, —O—, or —N— and with optional substituents onthe ring atoms including, but not limited to, halogens, halides,alkylhalides lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring optionally may be fused to oneor more of another heterocyclic, cycloalkyl or aryl ring(s).

The term “alkenyl” as used herein refers to an unsaturated straight,branched, or cyclic, primary, secondary, or tertiary hydrocarbon oftypically C₁ to C₁₀, that has one or more double bonds therein where thedouble bond can be unconjugated or conjugated to another unsaturatedgroup (e.g., a polyunsaturated alkenyl) and can be unsubstituted orsubstituted, with multiple degrees of substitution being allowed.Substituents on alkenyl include, for example, halides, alkylhalides,lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, silyloxyoptionally substituted by alkoxy, alkyl, or aryl, silyl optionallysubstituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lowerperfluoroalkyl, multiple degrees of substitution being allowed. Forexample, and without limitation, the alkenyl can be vinyl, allyl,butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl,decenyl, undecenyl, dodecenyl, heptadecenyl, octadecenyl, nonadecenyl,eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracisenyl,pentacosenyl, phytyl, the branched chain isomers thereof, andpolyunsaturated alkenes including octadec-9,12,-dienyl,octadec-9,12,15-trienyl, and eicos-5,8,11,14-tetraenyl. In certainembodiments, alkenyl groups are optionally substituted with one or moremoieties selected from the group consisting of hydroxyl, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate.

The term “alkynyl” refers to an unsaturated straight, branched, orcyclic, primary, secondary, or tertiary hydrocarbon having from abouttwo to about fifty carbons, typically C₁ to C₁₀, and at least onecarbon-carbon triple bond, and wherein the alkynyl is optionallysubstituted with substituents comprising, hydroxyl, alkylamino,arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,phosphonic acid, phosphate, phosphonate, lower alkyl, lower alkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl,or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

The terms “alkylamino” or “arylamino” as used herein refer to an aminogroup that has one or two alkyl or aryl substituents, respectively. Forexample, alkylamino is a substituent such as —NH(CH₃), N(CH₃)₂, etc. andarylamino is a substituent such as —NH(Ph), N(Ph)₂.

The term “aryl” as used herein refers to a carbocyclic aromatic ring,such as phenyl, biphenyl, naphthyl, or anthracenyl. The term includesboth substituted and unsubstituted moieties and includes for example, anoptionally substituted benzene ring or an optionally substituted benzenering system fused to one or more optionally substituted benzene rings,with multiple degrees of substitution being allowed. The aryl group canalso be substituted with one or more moieties comprising: hydroxyl,amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonicacid, sulfate, phosphonic acid, phosphate, or phosphonate. Substituentsalso include, but are not limited to, lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, amino sulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Examples of aryl include, but arenot limited to, phenyl, 2-napthyl, 1-naphthyl, 1-anthracenyl, and thelike.

The term “acyl” as used herein refers to a carboxylic acid ester,represented by the formula —C(O)O—R* in which R* is selected fromstraight, branched, or cyclic alkyl or lower alkyl, alkoxyalkylincluding methoxymethyl, aralkyl including benzyl, aryloxyalkyl such asphenoxymethyl, aryl including phenyl optionally substituted with halogen(F, Cl, Br, I), C₁ to C₄ alkyl or C₁ to C₄ alkoxy, sulfonate esters suchas alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di ortriphosphate ester, trityl or monomethoxytrityl, substituted benzyl,trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Arylgroups in the esters optimally comprise a phenyl group. R* may beselected from alkyl, alkenyl, alkynyl, carbocycle, heterocycle, any ofwhich are optionally substituted by a substituent described herein.

As used herein, the term “alkoxy” refers to an optionally substitutedstraight or branched chain alkyl-O— group wherein alkyl is as previouslydefined. For example, C₁₋₁₀ alkoxy means a straight or branched alkoxycontaining at least 1, and at most 10, carbon atoms. Examples of“alkoxy” as used herein include, but are not limited to, methoxy,ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy,2-methylprop-2-oxy, pentoxy and hexyloxy. A C₁₋₄alkoxy group ispreferred, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or 2-methylprop-2-oxy. Alkoxy may be substituted with one ormore substituents described herein.

As used herein, the term “aryloxy” refers to an optionally substituted—O-aryl-O— group wherein aryl is as previously defined. Exemplaryaryloxy groups include, but are not limited to, phenoxy (phenyl-O—).Aryloxy may be substituted by one or more substituents described herein.

As used herein, the term “heteroaryl” refers to an aromatic heterocycle.Heteroaryl may be optionally substituted. In certain embodiments,heteroaryl refers to an aromatic heterocycle comprising one or moreheteroatoms. Heteroatoms may include, for example, N, O, Si, P, B, and Satoms. As used herein, the heteroaryl ring may be selected frommonocyclic or bicyclic and fused or bridged ring systems rings whereinat least one of the rings in the ring system is aromatic, i.e., itcontains a cyclic, delocalized (4n+2) π-electron system in accordancewith the Hückel theory. The heteroatom(s) in the heteroaryl radical maybe optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Heteroaryl groups having a total of from about 5 to about 14carbon atom ring members and heteroatom ring members (and allcombinations and subcombinations of ranges and specific numbers ofcarbon and heteroatom ring members) are preferred. Heteroaryl groupshaving a total of from about 5 to about 10 carbon atom ring members andheteroatom ring members (and all combinations and subcombinations ofranges and specific numbers of carbon and heteroatom ring members) aremore preferred. Exemplary heteroaryl groups include, but are not limitedto, pyrryl, furyl, pyridyl, pyridine-N-oxide, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl,isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl,and isoxazolyl. Unless stated otherwise specifically in thespecification, the term “heteroaryl” is meant to include heteroarylradicals as defined above which are optionally substituted by one ormore substituents such as those substituents described herein.

As used herein, the term “heteroarylalkyl” refers to an optionallysubstituted moiety comprising an alkyl radical bearing a heteroarylsubstituent, each as defined above, having from about 6 to about 50carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 6 to about 25carbon atoms being preferred. Non-limiting examples include2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

In certain embodiments, a heterocycloalkyl ring system has a total offrom about 3 to about 14 carbon atom ring members and heteroatom ringmembers (and all combinations and subcombinations of ranges and specificnumbers of carbon and heteroatom ring members). In other embodiments,the heterocycloalkyl groups may be fused to one or more aromatic rings.In yet other embodiments, heterocycloalkyl moieties are attached via aring carbon atom to the rest of the molecule. Exemplary heterocycloalkylgroups include, but are not limited to, azepanyl, tetrahydrofuranyl,hexahydropyrimidinyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,imidazolidinyl, diazolidinyl, piperazinyl, 2-oxo-morpholinyl,morpholinyl, 2-oxo-piperidinyl, piperadinyl, decahydroquinolyl,octahydrochromenyl, octahydro-cyclopentapyranyl,1,2,3,4,-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinazolinyl,octahydro-[2]pyridinyl, decahydro-cyclooctafuranyl,1,2,3,4-tetrahydroisoquinolyl, 2-oxoimidazolidinyl, and imidazolidinyl.In some embodiments, two moieties attached to a heteroatom may be takentogether to form a heterocycloalkyl ring. In certain of theseembodiments, 1 or 2 of the heterocycloalkyl ring carbon atoms may bereplaced by other moieties which contain either one (—O—, —S—, —N(R)—)or two (—N(R)—C(═O)—, or —C(═O)N(R)—) ring replacement atoms. When amoiety containing one ring replacement atom replaces a ring carbon atom,the resultant ring, after replacement of a ring atom by the moiety, willcontain the same number of ring atoms as the ring before ring atomreplacement. When a moiety containing two ring replacement atomsreplaces a ring carbon atom, the resultant ring after replacement willcontain one more ring atom than the ring prior to replacement by themoiety. For example, when a piperidine ring has one of its ring carbonatoms replaced by —N(R) C(═O)—, the resultant ring is a 7-membered ringcontaining 2 ring nitrogen atoms and the carbon of a carbonyl group inaddition to 4 other carbon ring atoms (CH₂ groups) from the originalpiperidine ring. “Cycloaliphatic” means a saturated or unsaturated,non-aromatic hydrocarbon moiety having from 1 to 3 rings, each ringhaving from 3 to 8 carbon atoms. Cycloaliphatic includes cycloalkyl,cycloalkenyl and cycloalkynyl monocyclic or polycyclic rings.“Cyclo-alkenyl” means a cycloaliphatic moiety in which at least one ringhas at least one carbon-carbon double bond. “Cycloalkynyl” means acycloaliphatic moiety in which at least one ring has at least onecarbon-carbon triple bond. By way of illustration, cycloaliphaticmoieties include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, and adamantyl. Preferred cycloaliphatic moieties includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloaliphatic” means a cycloaliphatic moiety wherein, in atleast one ring thereof, up to three carbons have been replaced with aheteroatom independently selected from N, O, or S, where the N and Soptionally may be oxidized and the N optionally may be quaternized.Exemplary heterocycloaliphatic moieties include aziridinyl, azetidinyl,1,3-dioxanyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl,tetrahydro-1,1-dioxothienyl, 1,4-dioxanyl, thietanyl, and the like.

“Hydroxyalkyl,” “haloalkyl,” “alkylaryl,” “cyanoaryl,” and the like meanan alkyl, aryl, etc., moiety, as the case may be, substituted with oneor more of the identified substituent (hydroxyl, halo, etc., as the casemay be).

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms. The term“substituted” as used herein refers to substitution with the namedsubstituent or substituents, multiple degrees of substitution beingallowed unless otherwise stated.

The term “optionally substituted” means that the group in question maybe unsubstituted or it may be substituted one or several times, such as1 to 3 times or 1 to 5 times. For example, an alkyl group that is“optionally substituted” with 1 to 5 chloro atoms, may be unsubstituted,or it may contain 1, 2, 3, 4, or 5 chlorine atoms. Typically,substituted chemical moieties include one or more substituents thatreplace hydrogen. Exemplary substituents include, for example, halo(e.g., F, Cl, Br, I), amino (NH₂), alkyl, alkylamino, cycloalkyl,alkylcycloalkyl, alkenyl, alkynyl, haloalkyl including trifluoroalkyl,aralkyl, aryl, heteroaryl, heteroarylalkyl, spiroalkyl, heterocyclyl,heterocycloalkyl, hydroxyl (—OH), alkoxyl, aryloxyl, aralkoxyl, nitro(—NO₂), cyano (—CN), amino (—NH₂), N-substituted amino (—NHR″),N,N-disubstituted amino (—N(R″)R″), carboxyl (—COOH), —C(═O)R″, —OR″,—C(═O)OR″, —C(═O)NHSO₂R″, —NHC(═O)R″, aminocarbonyl (—C(═O)NH₂),N-substituted aminocarbonyl (C(═O)NHR″), N,N-disubstituted aminocarbonyl(—C(═O)N(R″)R″), thiolato (SR″), sulfonic acid and its esters (—SO₃R″),phosphonic acid and its mono-ester (—P(═O)(OR″)(OH) and di-esters(—P(═O)(OR″)(OR″), —S(═O)₂R″, —S(═O)₂NH₂, —S(═O)₂NHR″, —S(═O)₂NR″R″,—SO₂NHC(═O)R″, NHS(═O)₂R″, —NR″S(═O)₂R″, —CF₃, —CF₂CF₃, —NHC(═O)NHR″,—NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, —NR″C(═O)R″ and the like.In relation to the aforementioned substituents, each moiety “R” can be,independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl,heteroaryl, or heterocycloalkyl, or when (R″(R″)) is attached to anitrogen atom, R″ and R″ can be taken together with the nitrogen atom towhich they are attached to form a 4- to 8-membered nitrogen heterocycle,wherein the heterocycloalkyl ring is optionally interrupted by one ormore additional —O—, —S—, —SO, —SO₂—, —NH—, —N(alkyl)-, or —N(aryl)groups, for example. In certain embodiments, chemical moieties aresubstituted by at least one optional substituent, such as those providedhereinabove. In the present invention, when chemical moieties aresubstituted with optional substituents, the optional substituents arenot further substituted unless otherwise stated. For example, when an Rgroup is an alkyl moiety, it is optionally substituted, based on thedefinition of “alkyl” as set forth herein. In some embodiments, when Ris alkyl substituted with optional aryl, the optional aryl substituentis not further substituted.

By way of illustration, substituents include, but are not limited to,alkyl (e.g. methyl, ethyl), alkylamino, alkenyl (especially allyl),alkynyl, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, halo(especially fluoro), haloalkyl (especially trifluoromethyl), hydroxyl,hydroxyalkyl (especially hydroxyethyl), cyano, nitro, alkoxy,—O(hydroxyalkyl), —O(haloalkyl) (especially —OCF₃), —O(cycloalkyl),—O(heterocycloalkyl), —O(aryl), alkylthio, arylthio, ═O, ═NH, ═N(alkyl),═NOH, ═NO(alkyl), —C(═O)(alkyl), —C(═O)H, —CO₂H, —C(═O)NHOH,—C(═O)O(alkyl), —C(═O)O(hydroxyalkyl), —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —OC(═O)(alkyl), —OC(═O)(hydroxyalkyl), —OC(═O)O(alkyl),—OC(═O)O(hydroxyalkyl), —OC(═O)NH₂, —OC(═O)NH(alkyl), —OC(═O)N(alkyl)₂,azido, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(aryl), —NH(hydroxyalkyl),—NHC(═O)(alkyl), —NHC(═O)H, —NHC(═O)NH₂, —NHC(═O)NH(alkyl),—NHC(═O)N(alkyl)₂, —NHC(═NH)NH₂, —OSO₂(alkyl), —SH, —S(alkyl), —S(aryl),—S(cycloalkyl), —S(═O)alkyl, —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl),—SO₂N(alkyl)₂, and the like.

Where the moiety being substituted is an aliphatic moiety, substituentsinclude, but not limited to: aryl, heteroaryl, cycloaliphatic,heterocycloaliphatic, halo, hydroxyl, cyano, nitro, alkoxy,—O(hydroxyalkyl), —O(haloalkyl), —O(cycloalkyl), —O(heterocycloalkyl),—O(aryl), alkylthio, arylthio, ═O, ═NH, ═N(alkyl), ═NOH, ═NO(alkyl),—CO₂H, —C(═O)NHOH, —C(═O)O(alkyl), —C(═O)O(hydroxyalkyl), —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —OC(═O)(alkyl), —OC(═O)(hydroxyalkyl),—OC(═O)O(alkyl), —OC(═O)O(hydroxyalkyl), —OC(═O)NH₂, —OC(═O)NH(alkyl),—OC(═O)N(alkyl)₂, azido, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(aryl),—NH(hydroxyalkyl), —NHC(═O)(alkyl), —NHC(═O)H, —NHC(═O)NH₂,—NHC(═O)NH(alkyl), —NHC(═O)N(alkyl)₂, —NHC(═NH)NH₂, —OSO₂(alkyl), —SH,—S(alkyl), —S(aryl), —S(═O)alkyl, —S(cycloalkyl), —SO₂(alkyl), —SO₂NH₂,—SO₂NH(alkyl), and —SO₂N(alkyl)₂. More preferred substituents are halo,hydroxyl, cyano, nitro, alkoxy, —O(aryl), ═O, ═NOH, ═NO(alkyl),—OC(═O)(alkyl), —OC(═O)O(alkyl), —OC(═O)NH₂, —OC(═O)NH(alkyl),—OC(═O)N(alkyl)₂, azido, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(aryl),—NHC(═O)(alkyl), —NHC(═O)H, —NHC(═O)NH₂, —NHC(═O)NH(alkyl),—NHC(═O)N(alkyl)₂, and —NHC(═NH)NH₂. Especially preferred are phenyl,cyano, halo, hydroxyl, nitro, C₁-C₄alkyoxy, O(C₂-C₄ alkylene)OH, andO(C₂-C₄ alkylene)halo.

Where the moiety being substituted is a cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl moiety, substituents include,but not limited to: alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl,hydroxyalkyl, cyano, nitro, alkoxy, —O(hydroxyalkyl), —O(haloalkyl),—O(aryl), —O(cycloalkyl), —O(heterocycloalkyl), alkylthio, arylthio,—C(═O)(alkyl), —C(═O)H, —CO₂H, —C(O)NHOH, —C(═O)O(alkyl),—C(═O)O(hydroxyalkyl), —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂,—OC(═O)(alkyl), —OC(═O)(hydroxyalkyl), —OC(═O)O(alkyl),—OC(═O)O(hydroxyalkyl), —OC(═O)NH₂, —OC(═O)NH(alkyl), —OC(═O)N(alkyl)₂,azido, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(aryl), —NH(hydroxyalkyl),—NHC(═O)(alkyl), —NHC(═O)H, —NHC(═O)NH₂, —NHC(═O)NH(alkyl),—NHC(═O)N(alkyl)₂, —NHC(═NH)NH₂, —OSO₂(alkyl), —SH, —S(alkyl), —S(aryl),—S(cycloalkyl), —S(═O)alkyl, —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl), and—SO₂N(alkyl)₂. In some embodiments, substituents are alkyl, alkenyl,halo, haloalkyl, hydroxyl, hydroxyalkyl, cyano, nitro, alkoxy,—O(hydroxyalkyl), —C(═O)(alkyl), —C(═O)H, —CO₂H, —C(═O)NHOH,—C(═O)O(alkyl), —C(═O)O(hydroxyalkyl), —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —OC(═O)(alkyl), —OC(═O)(hydroxyalkyl), —OC(═O)O(alkyl),—OC(═O)O(hydroxyalkyl), —OC(═O)NH(alkyl), —OC(═O)N(alkyl)₂, —NH₂,—NH(alkyl), —N(alkyl)₂, —NH(aryl), —NHC(═O)(alkyl), —NHC(═O)H,—NHC(═O)NH₂, —NHC(═O)NH(alkyl), —NHC(═O)N(alkyl)₂, and —NHC(═NH)NH₂. Insome embodiments, substituents are C₁-C₄ alkyl, cyano, nitro, halo, andC₁-C₄alkoxy.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if theR₅ group is shown to be substituted with 0-2 substituents, then saidgroup may optionally be substituted with up to two substituents and eachsubstituent may be selected independently from the definition ofoptionally substituted defined above. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)—. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a phenyl ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible.Tautomers are included within the scope of the compounds describedherein. The compounds presented herein, in certain embodiments, exist astautomers. For example, where an alkene carbon of a compound issubstituted with a hydroxyl group, both the enol and keto forms of thecompound are included within the intended scope of the compoundsdescribed herein. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C).Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N,¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br,⁸¹Br, ¹²⁵I are all contemplated. All isotopic variations of thecompounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6 (10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64 (1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

As used herein, a “pharmaceutically acceptable” component/carrier etc isone that is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation, and allergicresponse) commensurate with a reasonable benefit/risk ratio.

By “therapeutically effective amount” is meant an amount of a compoundof the present invention effective to yield the desired therapeuticresponse. For example, an amount effective to delay the growth of acancer, either a sarcoma or lymphoma, or to shrink the cancer or preventmetastasis. The specific safe and effective amount or therapeuticallyeffective amount will vary with such factors as the particular conditionbeing treated, the physical condition of the patient, the type of mammalor animal being treated, the duration of the treatment, the nature ofconcurrent therapy (if any), and the specific formulations employed andthe structure of the compounds or its derivatives.

The term “prodrug” refers to any derivative of a compound of theembodiments that is capable of directly or indirectly providing acompound of the embodiments or an active metabolite or residue thereofwhen administered to a subject. Particularly favored derivatives andprodrugs are those that increase the bioavailability of the compounds ofthe embodiments when such compounds are administered to a subject (e.g.,by allowing an orally administered compound to be more readily absorbedinto the blood) or which enhance delivery of the parent compound to abiological compartment (e.g., the brain or lymphatic system) relative tothe parent species. A general overview of prodrugs is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible.

The term “pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only, sodium,potassium, calcium, magnesium, ammonium, and tetraalkylammonium, andwhen the molecule contains a basic functionality, salts of organic orinorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, and oxalate. Suitable salts include thosedescribed in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook ofPharmaceutical Salts Properties, Selection, and Use; 2002.

“Treatment” is an intervention performed with the intention ofpreventing the development or altering the pathology or symptoms of adisorder. Accordingly, “treatment” refers to both therapeutic treatmentand prophylactic or preventative measures. “Treatment” may also bespecified as palliative care. Those in need of treatment include thosealready with the disorder as well as those in which the disorder is tobe prevented. In tumor (e.g., cancer) treatment, a therapeutic agent maydirectly decrease the pathology of tumor cells, or render the tumorcells more susceptible to treatment by other therapeutic agents, e.g.,radiation and/or chemotherapy. Accordingly, “treating” or “treatment” ofa state, disorder or condition includes: (1) preventing or delaying theappearance of clinical symptoms of the state, disorder or conditiondeveloping in a human or other mammal that may be afflicted with orpredisposed to the state, disorder or condition but does not yetexperience or display clinical or subclinical symptoms of the state,disorder or condition; (2) inhibiting the state, disorder or condition,i.e., arresting, reducing or delaying the development of the disease ora relapse thereof (in case of maintenance treatment) or at least oneclinical or subclinical symptom thereof; or (3) relieving the disease,i.e., causing regression of the state, disorder or condition or at leastone of its clinical or subclinical symptoms. The benefit to anindividual to be treated is either statistically significant or at leastperceptible to the patient or to the physician.

The terms “patient”, “subject” or “individual” are used interchangeablyherein, and refers to a mammalian subject to be treated, with humanpatients being preferred. In certain embodiments, the methods of theinvention find use in experimental animals, in veterinary application,and in the development of animal models for disease, including, but notlimited to, rodents including mice, rats, and hamsters; and primates.

TLR8 Agonists

TLR8 is expressed predominantly in myeloid dendritic cells, monocytes,and monocyte-derived dendritic cells (Bekeredjian-Ding, I. et al. J.Immunol. 2006, 176, 7438-7446; Warshakoon, H. J. et al. Hum. Vaccin.2009, 5, 381-394). Engagement by TLR8 agonists evokes a dominantproinflammatory cytokine profile, including tumor necrosis factor-α(TNF-α), interleukin (IL)-12, and IL-18, and appear uniquely potent inenhancing the production of Th1-polarizing cytokines TNF-α and IL-12 inAPCs (Bohnenkamp, H. R. et al. Cell. Immunol. 2007, 247, 72-84; Philbin,V. J. et al. Biochem. Soc. Trans. 2007, 35, 1485-1491; Saruta, M. et al.Eur. J. Immunol. 2009, 39, 2195-2202). Small molecule agonists of TLR8include: 2,3-diamino-furo[2,3-c]pyridines (Salunke, D. B. et al. J. Med.Chem. 2012, 55, 8137-8151), 4-amino-furo[2,3-c]quinolines (Kokatla, H.P. et al. J. Med. Chem. 2013, 56, 6871-6885), 3-alkyl-quinoline-2-amines(Kokatla, H. P. et al. Chem. Med. Chem. 2014, 9, 719-723), and1-alkyl-2-aminobenzimidazoles (Beesu, M. et al. J. Med. Chem. 2014, 57,7325-7341), all of which are pure TLR8 agonists with no detectableactivity at TLR7.

Crystal structures of the ectodomain of human TLR8 (hTLR8)co-crystallized with two regioisomers of dual TLR7/8-agonisticN1-aminomethylbenzyl-substituted imidazoquinolines (1, 2) showed subtledifferences in their interactions in the binding site of hTLR8 (FIG. 1);The N¹-substituent of 1 was observed to H-bond with a backbone carbonylgroup, while in 2, a stronger salt-bridge was present, which fullyexplained the higher TLR8 activity of 2.

The present disclosure provides a library of compounds and resultingcompositions having TLR8-specific agonistic activity.

In certain aspects, a compound of the disclosure is represented byFormula (II):

or a salt thereof, wherein:

R¹, R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of: H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, optionally substituted C₃₋₂₀carbocycle, and optionally substituted 3- to 20-membered heterocycle;

R⁶ is selected from the group consisting of —OR¹¹, —N(R¹¹)₂, —SR¹¹,optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R⁷ and R⁸ are independently selected from H, optionally substitutedC₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, optionallysubstituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle andoptionally substituted 3- to 12-membered heterocycle;

R¹⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted C₃₋₁₂ carbocycle and optionally substituted 3- to12-membered heterocycle; and

R¹¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

certain embodiments, for a compound or salt of Formula (II), at leastone of R¹ and R³ is selected from the group consistingof —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl,optionally substituted C₃₋₂₀ carbocycle, and optionally substituted 3-to 20-membered heterocycle. In certain embodiments, for a compound orsalt of Formula (II), at least one of R¹ and R³ may be selected from thegroup consistingof —OR¹⁰, —N(R¹⁰)₂, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl. Incertain embodiments, at least one of R¹ and R³ is selected from thegroup consisting of optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl. Incertain embodiments, at least one of R¹ and R³ is selected from thegroup consisting of substituted C₁₋₂₀ alkyl, substituted C₂₋₂₀ alkenyl,and substituted C₂₋₂₀ alkynyl. In certain embodiments, at least one ofR¹ and R³ is optionally substituted C₁₋₂₀ alkyl. In certain embodiments,at least one of R¹ and R³ is substituted C₁₋₂₀ alkyl. In certainembodiments, R¹ is optionally substituted C₁₋₁₀ alkyl. In certainembodiments, R¹ is optionally substituted C₁₋₅ alkyl. In certainembodiments, R¹ is substituted C₁₋₅ alkyl. In certain embodiments for acompound or salt of Formula (II), R¹ is selected from the groupconsisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,

—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.

In certain embodiments for a compound or salt of Formula (II), R¹ isoptionally substituted C₁₋₂₀ alkyl, wherein optional substituents areone or more substituents independently selected from the groupconsisting of: halogen, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein carbocycle and heterocycle are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isoptionally substituted C₁₋₂₀ alkyl, wherein the alkyl is substituted bya C₃₋₁₂ carbocycle, wherein the carbocycle is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isoptionally substituted C₁₋₂₀ alkyl, wherein the alkyl is substituted bya C₃₋₁₂ carbocycle, wherein the carbocycle is optionally substitutedwith one or more substituents selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₂₀ alkyl, wherein the alkyl is substituted by a C₃₋₁₂ carbocycle,wherein the carbocycle is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁵⁰)₂, and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₂₀ alkyl, wherein the alkyl is substituted by a C₃₋₁₂ carbocycle,wherein the carbocycle is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁵⁰)₂, and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.

In certain embodiments for a compound or salt of Formula (II), R¹ issubstituted with —N(R⁵⁰)₂. In certain embodiments for a compound or saltof Formula (II), R¹ is selected from:

In certain embodiments for a compound or salt of Formula (II), R¹ isselected from:

In some embodiments for a compound or salt of Formula (II), R¹ isselected from H, halogen, and —CN. In some embodiments, R¹ is hydrogen.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₃₋₂₀ carbocycle or 3- to20-membered heterocycle any of which is substituted with —N(R⁵⁰)₂; R³ isselected from H, halogen, and —CN, such as R³ is hydrogen; and R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R¹is C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, any of which issubstituted with —N(R⁵⁰)₂; R³ is selected from H, halogen, and —CN, suchas R³ is hydrogen; and R⁵⁰ at each occurrence is independently selectedfrom the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R¹ is C₁₋₂₀ alkyl substituted with —N(R⁵⁰)₂, R³is selected from H, halogen, and —CN, such as R³ is hydrogen; and R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen.For a compound or salt of Formula (II), R¹ may be C₁₋₂₀ alkylsubstituted with C₃₋₁₂ carbocycle or 3- to 12-membered heterocycle,wherein C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R¹⁰)₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and—C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂—N(R⁵⁰)₂; R³ is selected from H, halogen, and—CN, such as R³ is hydrogen; and R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₂₀ alkyl substituted with C₃₋₁₂ carbocycle, wherein the C₃₋₁₂carbocycle is optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂—N(R⁵⁰)₂; R³ is selected from H,halogen, and —CN, such as R³ is hydrogen; and R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments for a compound orsalt of Formula (II), R¹ is C₁₋₁₀ alkyl substituted with aryl, whereinthe aryl is optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂—N(R⁵⁰)₂; R³ is selected from H,halogen, and —CN, such as R³ is hydrogen; and R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.For a compound or salt of Formula (II), R³ may be optionally substitutedC₁₋₁₀ alkyl. In certain embodiments, R³ is optionally substituted C₁₋₅alkyl.For a compound or salt of Formula (II), R³ may be selected from thegroup consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-membered heterocycleoptional substituents are one or more substituents independentlyselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R³ isoptionally substituted C₁₋₂₀ alkyl, wherein optional substituents areone or more substituents independently selected from the groupconsisting of: halogen, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R³ isoptionally substituted C₁₋₂₀ alkyl, wherein the alkyl is substituted bya C₃₋₁₂ carbocycle, wherein the carbocycle is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R³ isoptionally substituted C₁₋₂₀ alkyl, wherein the alkyl is substituted bya C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle is optionallysubstituted with one or more substituents selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, and—C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R³ is C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the carbocycle is substitutedwith one or more substituents selected from the group consisting ofC₁₋₁₀ alkyl and —C₁₋₁₀ alkyl-N(R⁵⁰)₂, and wherein R⁵⁰ at each occurrenceis independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R³ is C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the carbocycle is substitutedwith one or more substituents selected from the group consisting ofC₁₋₁₀ alkyl and —C₁₋₁₀ alkyl-N(R⁵⁰)₂, and wherein R⁵⁰ at each occurrenceis independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R³ is substituted with —N(R⁵⁰)₂. In certainembodiments, R³ is selected from:

In certain embodiments, R³ is selected from:

In certain embodiments, R³ is selected from H, halogen, and —CN. Incertain embodiments, R³ is hydrogen. In certain embodiments, R³ ishalogen, wherein halogen is selected from fluorine, chloride, andbromine. In certain embodiments, R³ is —CN.In certain embodiments, R¹ is selected from H, halogen, and —CN. Incertain embodiments, R¹ is hydrogen. In certain embodiments, R¹ ishalogen, wherein halogen is selected from fluorine, chloride, andbromine. In certain embodiments, R¹ is —CN.In certain embodiments for a compound or salt of Formula (II), R³ isC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₃₋₂₀ carbocycle or 3- to20-membered heterocycle any of which is substituted with —N(R⁵⁰)₂; R¹ isselected from H, halogen, and —CN, such as R¹ is hydrogen; and R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R³is C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, any of which issubstituted with —N(R⁵⁰)₂; R¹ is selected from H, halogen, and —CN, suchas R¹ is hydrogen; and R⁵⁰ at each occurrence is independently selectedfrom the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R³ is C₁₋₂₀ alkyl substituted with —N(R⁵⁰)₂, R¹is selected from H, halogen, and —CN, such as R¹ is hydrogen; and R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen.For a compound or salt of Formula (II), R³ may be C₁₋₂₀ alkylsubstituted with C₃₋₁₂ carbocycle or 3- to 12-membered heterocycle,wherein C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and—C₁₋₁₀ alkyl-C(O)N(R″)₂—N(R⁵⁰)₂; R¹ is selected from H, halogen, and—CN, such as R¹ is hydrogen; and R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments for a compound or salt of Formula (II), R³ isC₁₋₂₀ alkyl substituted with C₃₋₁₂ carbocycle, wherein the C₃₋₁₂carbocycle is optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂—N(R⁵⁰)₂; R¹ is selected from H,halogen, and —CN, such as R¹ is hydrogen; and R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments for a compound orsalt of Formula (II), R³ is C₁₋₁₀ alkyl substituted with aryl, whereinthe aryl is optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂—N(R⁵⁰)₂; R¹ is selected from H,halogen, and —CN, such as R¹ is hydrogen; and R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.

In certain embodiments, for a compound or salt of Formula (II), R², R⁴,and R⁵ are independently selected from the group consisting of: H,

halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰, —C(O)R¹⁰,—C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, and optionallysubstituted C₁₋₂₀ alkyl. In certain embodiments, R², R⁴, and R⁵ areindependently selected from the group consisting of: H, halogen, —OR¹⁰,—N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, and optionally substituted C₁₋₂₀ alkyl. Incertain embodiments, R², R⁴, and R⁵ are independently selected from thegroup consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-membered heterocycleoptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R², R⁴,and R⁵ may be independently selected from the group consisting of:optionally substituted C₁₋₂₀ alkyl, wherein optional substituents ofC₁₋₂₀ alkyl are one or more substituents independently selected from thegroup consisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,C₃₋₁₂ carbocycle, wherein C₃₋₁₂ carbocycle is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —N(R⁵⁰)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰,and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R², R⁴,and R⁵ may be independently selected from the group consisting of:optionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen and C₃₋₁₂ carbocycle, wherein the C₃₋₁₂carbocycle is optionally substituted with one or more substituentsselected from the group consisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, and wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R² isC₁₋₂₀ alkyl or hydrogen. In certain embodiments, R² is hydrogen. Incertain embodiments, R⁴ is C₁₋₂₀ alkyl or hydrogen. In certainembodiments, R⁴ is hydrogen. In certain embodiments, R⁵ is C₁₋₂₀ alkylor hydrogen. In certain embodiments, R⁵ is hydrogen.In certain embodiments, for a compound or salt of Formula (II), R¹⁰ maybe selected from the group consisting of: optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, optionally substitutedC₂₋₂₀ alkynyl, wherein optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein carbocycle and heterocycle are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and optionally substituted C₃₋₂₀ carbocycle andoptionally substituted 3- to 20-membered heterocycle, wherein optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰,and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R¹⁰ maybe optionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰)))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and optionally substituted C₃₋₂₀ carbocycle, whereinthe C₃₋₂₀ carbocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —N(R⁵⁰)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰,and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (II), R¹⁰ isoptionally substituted C₁₋₂₀ alkyl. In certain embodiments, for acompound or salt of Formula (II), R¹⁰ may be optionally substitutedC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl optional substituents are one ormore substituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle. In certainembodiments, R¹⁰ is C₁₋₂₀ alkyl. In certain embodiments, R¹⁰ is C₁₋₁₀alkyl. In certain embodiments, R¹⁰ is C₁₋₅ alkyl.In certain embodiments, for a compound or salt of Formula (II), R⁶ maybe selected from the group consisting of optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionally substitutedC₂₋₂₀ alkynyl. In certain embodiments, R⁶ is selected from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₁₋₂₀ alkynyl. In certainembodiments, R⁶ is selected from the group consisting of optionallysubstituted C₁₋₁₀ alkyl. In certain embodiments, R⁶ is selected from thegroup consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andwherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments for a compound or salt of Formula (II), R⁶ isoptionally substituted C₁₋₂₀ alkyl. In certain embodiments, R⁶ is C₁₋₂₀alkyl. In certain embodiments, R⁶ is C₁₋₁₀ alkyl. In certainembodiments, R⁶ is C₁₋₆ alkyl. In certain embodiments, R⁶ is:

In certain embodiments for a compound or salt of Formula (II), R⁷ and R⁸may be independently selected from H and optionally substituted C₁₋₁₀alkyl. In certain embodiments, R⁷ and R⁸ are independently selected fromthe group consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andwherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments for a compound or salt of Formula (II), R⁷ and R⁸are independently optionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀alkyl optional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,and optionally substituted C₃₋₂₀ carbocycle wherein the C₃₋₂₀ carbocycleoptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —N(R⁵⁰)₂, —C₁₋₁₀alkyl-N(R⁵⁰)₂, and —C₁₋₁₀ alkyl-OR⁵⁰; and wherein R⁵⁰ at each occurrenceis independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R⁷ is hydrogen. Incertain embodiments, R⁸ is hydrogen. In certain embodiments, each of R⁷and R⁸ are hydrogen.In certain embodiments for a compound or salt of Formula (II), isrepresented by the

or a salt of any one thereof.In certain embodiments for a compound or salt of Formula (II),R¹, R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of: H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, wherein at least one of R¹ and R³ is selectedfrom the group consisting of —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, optionally substituted C₃₋₂₀carbocycle, and optionally substituted 3- to 20-membered heterocycle; R⁶is selected from the group consisting of —OR¹¹, —N(R¹¹)₂, —SR¹¹,optionally substituted C₁₋₂₀ alkyl; R⁷ and R⁸ are independently selectedfrom H, optionally substituted C₁₋₁₀alkyl, optionally substituted C₃₋₁₂carbocycle and optionally substituted 3- to 12-membered heterocycle; R¹⁰is independently selected at each occurrence from the group consistingof H, optionally substituted C₁₋₁₀ alkyl, optionally substituted C₃₋₁₂carbocycle and optionally substituted 3- to 12-membered heterocycle; andR″ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹, R²,R³, R⁴, and R⁵ are independently selected from the group consisting of:H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, optionally substituted C₁₋₂₀ alkyl,wherein at least one of R¹ and R³ is selected from the group consistingof —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₃₋₂₀ carbocycle, and optionally substituted 3- to20-membered heterocycle; R⁶ is optionally substituted C₁₋₂₀ alkyl; R⁷and R⁸ are independently selected from H, and optionally substitutedC₁₋₁₀ alkyl; R¹⁰ is independently selected at each occurrence from thegroup consisting of H, optionally substituted C₁₋₁₀ alkyl, andoptionally substituted C₃₋₁₂ carbocycle; and R″ is independentlyselected at each occurrence from the group consisting of optionallysubstituted C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II),R¹, R², R³, R⁴, and R⁵ are independently hydrogen or optionallysubstituted C₁₋₂₀ alkyl, wherein at least one of R¹ and R³ is selectedfrom the group consisting of —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, and optionallysubstituted C₁₋₂₀ alkyl; R⁶ is C₁₋₂₀ alkyl; R⁷ and R⁸ are both H; R¹⁰ isindependently selected at each occurrence from the group consisting ofH, and optionally substituted C₁₋₁₀ alkyl; and R¹¹ is independentlyselected at each occurrence from the group consisting of optionallysubstituted C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ ishydrogen or optionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkylis substituted by a C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle issubstituted with one or more substituents selected from the groupconsisting of C₁₋₁₀ alkyl and —C₁₋₁₀ alkyl-N(R⁵⁰)₂; R³ is hydrogen orC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁵⁰)₂, R², R, and R⁵ are independently hydrogen oroptionally substituted C₁₋₂₀ alkyl, wherein at least one of R¹ and R³ isselected from optionally substituted C₁₋₂₀ alkyl; wherein R⁵⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl; R⁶ is optionally substitutedC₁₋₂₀ alkyl; R⁷ is hydrogen or optionally substituted C₁₋₂₀ alkyl; R⁸ ishydrogen or optionally substituted C₁₋₂₀ alkyl; R¹⁰ is independentlyselected at each occurrence from the group consisting of H, andoptionally substituted C₁₋₁₀ alkyl; and R¹¹ is independently selected ateach occurrence from the group consisting of optionally substitutedC₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ ishydrogen or C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by aC₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle, e.g., phenyl, issubstituted with one or more substituents selected from the groupconsisting of C₁₋₁₀ alkyl and —C₁₋₁₀ alkyl-N(R⁵⁰)₂; R³ is hydrogen; R²,R⁴, and R⁵ are independently hydrogen or optionally substituted C₁₋₂₀alkyl; R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl; R⁶ isoptionally substituted C₁₋₁₀ alkyl, wherein the C₁₋₁₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —N(R⁵⁰)₂, and —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂;R⁷ is hydrogen or C₁₋₂₀ alkyl, e.g., methyl; R⁸ is hydrogen or C₁₋₂₀alkyl, e.g., methyl; R¹⁰ is independently selected at each occurrencefrom the group consisting of H, and optionally substituted C₁₋₁₀ alkyl;and R¹¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₂₀ alkyl substituted by one or more of substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR³⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂ OR⁵⁰; R³ is hydrogen; R², R⁴, and R⁵ are independentlyhydrogen or optionally substituted C₁₋₂₀ alkyl; R⁵⁰ at each occurrenceis independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl; R⁶ is C₁₋₁₀ alkyl; R¹⁰ is independentlyselected at each occurrence from the group consisting of H, and C₁₋₁₀alkyl; and R¹¹ is independently at each occurrence C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ isC₁₋₁₀ alkyl, e.g., C₁₋₅ alkyl, substituted by one or more ofsubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, and —N(R⁵⁰)₂; R³ is hydrogen; R², R⁴, and R⁵ areindependently hydrogen or optionally substituted C₁₋₂₀ alkyl; R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl; R⁶ is C₁₋₁₀ alkyl, e.g.,C₁₋₅ alkyl; R¹⁰ is independently selected at each occurrence from thegroup consisting of H, and C₁₋₁₀ alkyl; and R¹¹ is independently at eachoccurrence is C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ ishydrogen; R³ is C₁₋₂₀ alkyl, wherein the alkyl is substituted by aphenyl, wherein the phenyl is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁵⁰)₂; R², R⁴, and R⁵ are independently hydrogen or optionallysubstituted C₁₋₂₀ alkyl; wherein R⁵⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl; R⁶ is C₁₋₁₀ alkyl; R¹⁰ is independently selected at eachoccurrence from the group consisting of H, and C₁₋₁₀ alkyl; and R¹¹ isindependently selected at each occurrence C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R¹ ishydrogen; R³ is C₁₋₂₀ alkyl, wherein the alkyl is substituted by apyridyl, wherein the pyridyl is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁵⁰)₂; R², R⁴, and R⁵ are independently hydrogen oroptionally substituted C₁₋₂₀ alkyl; wherein R⁵⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl; R⁶ is C₁₋₁₀ alkyl; R¹⁰ is independentlyselected at each occurrence from the group consisting of H, and C₁₋₁₀alkyl; and R¹¹ is independently at each occurrence C₁₋₁₀ alkyl.In certain embodiments for a compound or salt of Formula (II), R³ isC₁₋₁₀ alkyl, e.g., C₁₋₅ alkyl, substituted by one or more ofsubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, and —N(R⁵⁰)₂; R¹ is hydrogen; R², R⁴, and R⁵ areindependently hydrogen or optionally substituted C₁₋₂₀ alkyl; R⁵⁰ ateach occurrence is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl; R⁶ is C₁₋₁₀ alkyl, e.g.,C₁₋₅ alkyl; R¹⁰ is independently selected at each occurrence from thegroup consisting of H, and C₁₋₁₀ alkyl; and R¹¹ is independently at eachoccurrence is C₁₋₁₀ alkyl.

In certain embodiments, a compound is represented by Formula (III):

or a salt thereof, wherein:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H, halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰,—C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionallysubstituted C₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀alkynyl, and optionally substituted 3- to 20-membered heterocycle,

R¹⁶ is selected from the group consisting of optionally substitutedC₁₋₂₀ alkyl, —OR²¹, —N(R²¹)₂, —SR²¹, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R¹⁷ and R¹⁸ are independently selected from the group consisting of H,optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀ alkynyl, optionally substitutedC₃₋₁₂ carbocycle and optionally substituted 3- to 12-memberedheterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₁₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

In certain embodiments, a compound is represented by Formula (III):

or a salt thereof, wherein:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H, halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰,—C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionallysubstituted C₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀alkynyl, and optionally substituted 3- to 20-membered heterocycle,

wherein at least one of R¹¹, R¹², R¹³, and R¹⁴ is selected from thegroup consisting of —OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionally substituted C₃₋₂₀carbocycle, optionally substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, and optionallysubstituted 3- to 20-membered heterocycle;

R¹⁶ is selected from the group consisting of optionally substitutedC₁₋₂₀ alkyl, —OR²¹, —N(R²¹)₂, —SR²¹, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R¹⁷ and R¹⁸ are independently selected from the group consisting of H,optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀ alkynyl, optionally substitutedC₃₋₁₂ carbocycle and optionally substituted 3- to 12-memberedheterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₁₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

In certain embodiments for a compound or salt of Formula (III), at leastone of R¹¹, R¹², R¹³, and R¹⁴ may be selected from the group consistingof —OR²⁰, —N(R²⁰)₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)R²⁰, —C(O)N(R²⁰)₂,—S(O)R²⁰, —S(O)R²⁰, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl. Incertain embodiments, at least one of R¹¹, R¹², R¹³, and R¹⁴ is selectedfrom the group consisting of optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀alkynyl. In certain embodiments, at least one of R¹¹, R¹², R¹³, and R¹⁴is optionally substituted C₁₋₂₀ alkyl. In certain embodiments, R¹¹ isoptionally substituted C₁₋₁₀ alkyl. In certain embodiments, R¹¹ isoptionally substituted C₁₋₅ alkyl. In certain embodiments, for acompound or salt of Formula (III), R¹¹ is selected from the groupconsisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰,—N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

In certain embodiments, for a compound or salt of Formula (III), R¹¹ isoptionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, wherein the C₃₋₁₂ carbocycle and 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

In certain embodiments, for a compound or salt of Formula (III), R¹¹ isoptionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and—C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹¹ isoptionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle isoptionally substituted with one or more substituents selected from thegroup consisting of C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂,and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹¹ isC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹¹ isC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹¹ issubstituted with —N(R⁶⁰)₂. In certain embodiments, R¹¹ is selected from:

In certain embodiments, for a compound or salt of Formula (III) R¹¹ isselected from:

In certain embodiments, for a compound or salt of Formula (III), R¹³ maybe optionally substituted C₁₋₁₀ alkyl. In certain embodiments, R isoptionally substituted C₁₋₅ alkyl.In certain embodiments, for a compound or salt of Formula (III), R¹³ isselected from the group consisting of: optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, optionally substitutedC₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyloptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰,—N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰,—C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, wherein the C₃₋₁₂ carbocycle and the 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-O R⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andoptionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁, alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹³ isoptionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, wherein the C₃₋₁₂ carbocycle and the 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR¹¹, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹³ isoptionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and—C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹³ isoptionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl issubstituted by a C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle isoptionally substituted with one or more substituents selected from thegroup consisting of C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂,and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹² isC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R¹³ is C₁₋₂₀ alkyl,wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂ carbocycle, whereinthe C₃₋₁₂ carbocycle is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹³ isC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R¹³ is C₁₋₂₀ alkyl,wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂ carbocycle, whereinthe C₃₋₁₂ carbocycle is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹ isC₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂carbocycle, wherein the C₃₋₁₂ carbocycle is substituted with one or moresubstituents selected from the group consisting of C₁₋₁₀ alkyl and—C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl. In certain embodiments, R¹³ is C₁₋₂₀ alkyl,wherein the C₁₋₂₀ alkyl is substituted by a C₃₋₁₂ carbocycle, whereinthe C₃₋₂ carbocycle is substituted with one or more substituentsselected from the group consisting of C₁₋₁₀ alkyl and —C₁₋₁₀alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), one ofR¹¹, R¹², R¹³, and R¹⁴ is substituted with —N(R⁶⁰)₂. In certainembodiments, one of R¹¹, R¹², R¹³, and R¹⁴ is selected from:

In certain embodiments, for a compound or salt of Formula (III), one ofR¹¹, R¹², R¹³ and R¹⁴ is selected from:

In certain embodiments, for a compound or salt of Formula (III), one ofR¹¹, R¹², R¹³, and R¹⁴ is selected from H, halogen, and —CN. In certainembodiments, R¹¹ is hydrogen. In certain embodiments, R¹¹ is halogen,wherein halogen is selected from fluorine, chloride, and bromine. Incertain embodiments, R¹¹ is —CN.In certain embodiments, for a compound or salt of Formula (III), R¹² ishydrogen. In certain embodiments, R¹² is halogen, wherein halogen isselected from fluorine, chloride, and bromine. In certain embodiments,R¹² is —CN. In certain embodiments, R¹³ is hydrogen. In certainembodiments, R¹³ is halogen, wherein halogen is selected from fluorine,chloride, and bromine. In certain embodiments, R¹³ is —CN. In certainembodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ is halogen,wherein halogen is selected from fluorine, chloride, and bromine. Incertain embodiments, R¹⁴ is —CN.In certain embodiments, for a compound or salt of Formula (III), R¹²,R¹⁴, and R¹⁵ are independently selected from the group consisting of: H,halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —S(O)₂R²⁰, —S(O)₂OR²⁰, and optionallysubstituted C₁₋₂₀ alkyl. In certain embodiments, R¹², R¹⁴, and R¹⁵ areindependently selected from the group consisting of: H, halogen, —OR²⁰,—N(R²⁰)₂, —SR²⁰, —CN, —NO₂, and optionally substituted C₁₋₂₀ alkyl. Incertain embodiments, R¹², R¹⁴, and R¹⁵ are independently selected fromthe group consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰,—N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹²,R¹⁴, and R¹⁵ may be independently selected from the group consisting of:optionally substituted C₁₋₂₀ alkyl, wherein the C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂,C₃₋₁₂ carbocycle, wherein the C₃₋₁₂ carbocycle is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —N(R⁶⁰)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰,and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹²,R¹⁴, and R¹⁵ may be independently selected from the group consisting of:optionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen and C₃₋₁₂ carbocycle, wherein C₃₋₁₂carbocycle is optionally substituted with one or more substituentsselected from the group consisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹² isC₁₋₂₀ alkyl or hydrogen. In certain embodiments, R¹² is hydrogen. Incertain embodiments, R¹⁴ is C₁₋₂₀ alkyl or hydrogen. In certainembodiments, R¹⁴ is hydrogen. In certain embodiments, R⁵ is C₁₋₂₀ alkylor hydrogen. In certain embodiments, R¹⁵ is hydrogen.In certain embodiments, for a compound or salt of Formula (III), R²⁰ maybe selected from the group consisting of: optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, optionally substitutedC₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyloptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰,—N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰,—C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, wherein the C₃₋₁₂ carbocycle and 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andoptionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R²⁰ maybe optionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —N(R⁶⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and optionally substituted C₃₋₂₀ carbocycle, whereinthe C₃₋₂₀ carbocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —N(R⁶))₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰,and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R²⁰ maybe optionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)O R⁶⁰, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, —C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle. In certain embodiments, R²⁰ is optionally substituted C₁₋₂₀alkyl. In certain embodiments, R²⁰ is C₁₋₂₀ alkyl. In certainembodiments, R²⁰ is C₁₋₁₀ alkyl. In certain embodiments, R²⁰ is C₁₋₅alkyl.In certain embodiments, for a compound or salt of Formula (III), R¹⁶ maybe selected from the group consisting of optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionally substitutedC₂₋₂₀ alkynyl. In certain embodiments, R¹⁶ is selected from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₁₋₂₀ alkynyl. In certainembodiments, R¹⁶ is selected from the group consisting of optionallysubstituted C₁₋₁₀ alkyl. In certain embodiments, R¹⁶ is selected fromthe group consisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and optionally substituted C₃₋₂₀ carbocycle andoptionally substituted 3- to 20-membered heterocycle, wherein the C₃₋₂₀carbocycle and 3- to 20-membered heterocycle optional substituents areone or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹⁶ isoptionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀ alkyl optionalsubstituents are one or more substituents independently selected fromthe group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂,—NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)O R⁶⁰, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, and wherein R⁶⁰ at each occurrence is independentlyselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀haloalkyl. In certain embodiments, R¹⁶ is optionally substituted C₁₋₂₀alkyl, wherein C₁₋₂₀ alkyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —C(O)N(R⁶⁰)₂,—S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, and wherein R⁶⁰ at each occurrence isindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, R¹⁶ is optionally substituted C₁₋₂₀ alkyl. Incertain embodiments, R¹⁶ is C₁₋₂₀ alkyl. In certain embodiments, R¹⁶ isC₁₋₁₀ alkyl. In certain embodiments, R¹⁶ is C₁₋₆ alkyl. In certainembodiments, R¹⁶ is:

In certain embodiments, for a compound or salt of Formula (III), R¹⁷ andR¹⁸ may be independently selected from H and optionally substitutedC₁₋₁₀alkyl. In certain embodiments, R¹⁷ and R¹⁸ are independentlyselected from the group consisting of: optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, optionally substitutedC₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyloptional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰,—N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰,—C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, wherein the C₃₋₁₂ carbocycle and 3- to12-membered heterocycle are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andoptionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰—N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,—C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂;and wherein R⁶⁰ at each occurrence is independently selected from thegroup consisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹⁷ andR¹⁸ are independently optionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀alkyl optional substituents are one or more substituents independentlyselected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, andoptionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and optionallysubstituted 3- to 20-membered heterocycle optional substituents are oneor more substituents independently selected from the group consistingof: halogen, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.In certain embodiments, for a compound or salt of Formula (III), R¹⁷ andR¹⁸ are independently optionally substituted C₁₋₂₀ alkyl, wherein C₁₋₂₀alkyl optional substituents are one or more substituents independentlyselected from the group consisting of: halogen, —CN, —NO₂, —OR⁶⁰, —SR¹¹,—N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂, —OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰,—C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰, optionally substituted C₃₋₂₀carbocycle, wherein C₃₋₂₀ carbocycle optional substituents are one ormore substituents independently selected from the group consisting of:halogen, —N(R⁶⁰)₂, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, and —C₁₋₁₀ alkyl-OR⁶⁰; andwherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl. In certainembodiments, R⁷ is hydrogen. In certain embodiments, R¹⁸ is hydrogen.

In one embodiment a compound comprises a compound of general structuralFormula I:

wherein: R₁, R₅ are independently: H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂, C_((m+1))H_((2m+1)),C_((m+1))H_((2m+1))NH₂, C_((m+1))H_((2m+1))CONH₂, C_((m+1))H_((2m+1)),CR′NH₂, C_((m+1))H_((2m+1))—C₄₋₂₀ aryl-C_((m+1))H_((2m+1))—NH₂,C_(m)H_(2m+2), C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₁₋₂₀ alkylamino, C₂₋₂₀ alkenyl,C₂₋₂₀ alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkylheterocycle, C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, where m is aninteger from 0 to 10, and b is an integer from 0 to 10.

The C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₄₋₂₀heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle, C₇₋₂₀ alkylheteroaryl, C₁₋₂₀ alkyoxyl is unsubstituted or optionally substitutedwith a functional group comprising H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, or an amino acid side chainor peptide fragment, the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle,C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, and the C₁₋₆ alkyl is optionallyinterrupted by one or more O, S, or N atoms, or one or more groupscomprising cycloalkyl, C_((m+1))H_((2m+1)), C_((m+1))H_((2m+1))NH₂,CH—C(O)—O—, —O—C(O)—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and—O—C(O)—NH—, R′ is H, OH, halogen, NO₂, —NH₂, CN, —COOH, heteroarylhaving 1 to 4 N, O and/or S atoms, C₄₋₂₀ aryl, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀ heterocycle or C₄₋₁₀ heteroaryl.

The groups R₂, R₃, and R₄ are independently: H, —OH, —NH₂, —CH₂, —COOH,—OR′, —NH₂, —NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂where m is an integer from 0 to 10, and b is an integer from 0 to 10,C₁₋₅₀ alkyl, the C₁₋₅₀ alkyl is unsubstituted or optionally substitutedwith a functional group comprising one or more of: H, —OH, —OR′, —NH₂,—NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, an amino acidside chain or peptide fragment, where R¹ is selected from radicalsconsisting of H, heteroaryl having 1 to 4 N, O and/or S atoms, C₁₋₂₀alkyl, C₁₋₂₀ alkylamino, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀heterocycle, C₄₋₁₀ heteroaryl, ammonium and salts thereof, sulfates,sulfonates, thiosulfonates, boronates, phosphates, phosphonate,guanidine, amidine, pyridine, pyridium, alkali metal groups, nitrates,chlorates, perchlorates, acetates, chloride, bromide, iodide and saltsthereof, an alkali metal salt of sulfonic acid; an alkali metal salt ofphosphonic acid; a pharmaceutically acceptable salt; a sugar or apolyhydroxy group.

In other embodiments, R₁ is selected from the group of: H, —OH, —NH₂,(CH₂)_(b)NH₂, C_((m+1))H_((2m+1)), C_((m+1))H_((2m+1))NH₂,C_((m+1))H_((2m+1))—CO—NH₂, C_((m+1))H_((2m+1)), CR′NH₂,C_((m+1))H_((2m+1))—C₄₋₂₀ aryl-C_((m+1))H_((2m+1))—NH₂, C₄₋₂₀ aryl,C₁₋₂₀ alkyl, C₁₋₂₀ alkylamino, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₄₋₂₀heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle, C₇₋₂₀ alkylheteroaryl, C₁₋₂₀ alkyoxyl, where m is an integer from 0 to 10, and b isan integer from 0 to 10.

In another embodiment, R₁ is C_((m+1))H_((2m+1))NH₂ where m is aninteger from 0 to 10, and b is an integer from 0 to 10, C₁₋₁₀ alkyl, orC₁₋₁₀ alkyl substituted with a functional group selected from the groupconsisting of —OH, —OR′, —NH₂, —NHR′, —NR′₂, —O—C(O)R′, —C(O)R′, —CF₃,and —OCF₃, where R¹ is selected from the groups consisting of H and C₁₋₅alkyl.

In one embodiment, R₁ is H, (CH₂)₂₋₅NH₂, a pentyl amine (C₅H₁₁NH₂), or aC₁₋₂₀ alkylamino having a formula (CH₂)_(b)NH₂ where b is an integerfrom 0 to 10. In another embodiment, the R₉ group is H or C₅H₁₁NH₂.

In another embodiment, the R₃ is H, (CH₂)₂₋₅NH₂ a pentyl amine(C₅H₁₁NH₂), or a C₁₋₂₀ alkylamino having a formula (CH₂)_(b)NH₂ where bis an integer from 0 to 10. In another embodiment, R₃ is H or C₅H₁₁NH₂.

In another embodiment, R₂, R₄ and R₅ are H.

Some of the exemplary compounds are listed on Table 1. For example, acomposition can comprise one of the following selected compounds. Thefollowing compounds are listed for demonstration purposes. The compoundsin the present disclosure include but are not limited to:

4-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine dihydrochloride (9a)

4-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine dihydrochloride (9b)

4-(4-Aminobutyl)-3-pentylquinolin-2-amine dihydrochloride (14a)

4-(5-Aminopentyl)-3-pentylquinolin-2-amine dihydrochloride (14b)

5-Benzyl-3-pentylquinolin-2-amine (17d)

5-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18a)

5-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18b)

5-(2-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18c)

3-((2-Amino-3-pentylquinolin-5-yl)methyl)benzamide (18d)

5-(3-(Aminomethyl)phenyl)-3-pentylquinolin-2-amine (20a)

5-(4-(Aminomethyl)phenyl)-3-pentylquinolin-2-amine (20b)

5-(3-Aminopropyl)-3-pentylquinolin-2-amine (23)

5-(4-Aminobutyl)-3-pentylquinolin-2-amine (34a)

5-(5-Aminopentyl)-3-pentylquinolin-2-amine (34b)

5-(6-Aminohexyl)-3-pentylquinolin-2-amine (34c)

4-(2-Amino-3-pentylquinolin-5-yl)butanamide (34d)

1-(4-(2-Amino-3-pentylquinolin-5-yl)butyl)guanidine (34e)

6-(4-Aminobutyl)-3-pentylquinolin-2-amine (35a)

6-(5-Aminopentyl)-3-pentylquinolin-2-amine (35b)

6-(6-Aminohexyl)-3-pentylquinolin-2-amine (35c)

7-(4-Aminobutyl)-3-pentylquinolin-2-amine (36a)

7-(5-Aminopentyl)-3-pentylquinolin-2-amine (36b)

7-(6-Aminohexyl)-3-pentylquinolin-2-amine (36c)

8-(4-Aminobutyl)-3-pentylquinolin-2-amine (37)

5,5′-(2-amino-3-pentylquinoline-5,7-diyl)bis(pentan-1-amine) (43)

In other embodiments, a pharmaceutical composition of a therapeuticallyeffective amount of one or more compounds of general Formulas I:

wherein: R₁, R₅ are independently: H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂, C_((m+1))H_((2m+1)),C_((m+1))H_((2m+1))NH₂, C_((m+1))H_((2m+1))CONH₂, C_((m+1))H_((2m+1)),CR′NH₂, C_((m+1))H_((2m+1))—C₄₋₂₀ aryl-C_((m+1))H_((2m+1))—NH₂,C_(m)H_(2m+2), C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₁₋₂₀ alkylamino, C₂₋₂₀ alkenyl,C₂₋₂₀ alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkylheterocycle, C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, where m is aninteger from 0 to 10, and b is an integer from 0 to 10;

the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₄₋₂₀heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle, C₇₋₂₀ alkylheteroaryl, C₁₋₂₀ alkyoxyl is unsubstituted or optionally substitutedwith a functional group comprising H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, or an amino acid side chainor peptide fragment, the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle,C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, and the C₁₋₆ alkyl is optionallyinterrupted by one or more O, S, or N atoms, or one or more groupscomprising cycloalkyl, C_((m+1))H_((2m+1)), C_((m+1))H_((2m+1))NH₂,CH—C(O)—O—, —O—C(O)—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and—O—C(O)—NH—, R′ is H, OH, halogen, NO₂, —NH₂, CN, —COOH, heteroarylhaving 1 to 4 N, O and/or S atoms, C₄₋₂₀ aryl, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀ heterocycle or C₄₋₁₀ heteroaryl; thegroups R₂, R₃, and R₄ are independently: H, —OH, —NH₂, —CH₂, —COOH,—OR′, —NH₂, —NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂where m is an integer from 0 to 10 and b is an integer from 0 to 10,C₁₋₅₀ alkyl, the C₁₋₅₀ alkyl is unsubstituted or optionally substitutedwith a functional group comprising one or more of: H, —OH, —OR′, —NH₂,—NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, an amino acidside chain or peptide fragment, where R¹ is selected from radicalsconsisting of H, heteroaryl having 1 to 4 N, O and/or S atoms, C₁₋₂₀alkyl, C₁₋₂₀ alkylamino, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀heterocycle, C₄₋₁₀ heteroaryl, ammonium and salts thereof, sulfates,sulfonates, thiosulfonates, boronates, phosphates, phosphonate,guanidine, amidine, pyridine, pyridium, alkali metal groups, nitrates,chlorates, perchlorates, acetates, chloride, bromide, iodide and saltsthereof, an alkali metal salt of sulfonic acid; an alkali metal salt ofphosphonic acid; a pharmaceutically acceptable salt; a sugar, apolyhydroxy group or prodrugs thereof.

In another embodiment, a TLR8-specific agonist comprises one or morecompounds of general Formula I:

wherein: R₁, R₅ are independently: H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂, C_((m+1))H_((2m+1)),C_((m+1))H_((2m+1))NH₂, C_((m+1))H_((2m+1))CONH₂, C_((m+1))H_((2m+1)),CR′NH₂, C_((m+1))H_((2m+1))—C₄₋₂₀ aryl-C_((m+1))H_((2m+1))—NH₂,C_(m)H_(2m+2), C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₁₋₂₀ alkylamino, C₂₋₂₀ alkenyl,C₂₋₂₀ alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkylheterocycle, C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, where m is aninteger from 0 to 10, and b is an integer from 0 to 10;

the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₄₋₂₀heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle, C₇₋₂₀ alkylheteroaryl, C₁₋₂₀ alkyoxyl is unsubstituted or optionally substitutedwith a functional group comprising H, —OH, —OR′, —NH₂, —NHR′, —NR′₂,—SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, or an amino acid side chainor peptide fragment, the C₄₋₂₀ aryl, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀alkynyl, C₄₋₂₀ heterocycle, C₄₋₂₀ heteroaryl, C₄₋₂₀ alkyl heterocycle,C₇₋₂₀ alkyl heteroaryl, C₁₋₂₀ alkyoxyl, and the C₁₋₆ alkyl is optionallyinterrupted by one or more O, S, or N atoms, or one or more groupscomprising cycloalkyl, C_((m+1))H_((2m+1)), C_((m+1))H_((2m+1))NH₂,CH—C(O)—O—, —O—C(O)—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and—O—C(O)—NH—, R′ is H, OH, halogen, NO₂, —NH₂, CN, —COOH, heteroarylhaving 1 to 4 N, O and/or S atoms, C₄₋₂₀ aryl, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀ heterocycle or C₄₋₁₀ heteroaryl;the groups R₂, R₃, and R₄ are independently: H, —OH, —NH₂, —CH₂, —COOH,—OR′, —NH₂, —NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, (CH₂)_(b)NH₂where m is an integer from 0 to 10 and b is an integer from 0 to 10,C₁₋₅₀ alkyl, the C₁₋₅₀ alkyl is unsubstituted or optionally substitutedwith a functional group comprising one or more of: H, —OH, —OR′, —NH₂,—NHR′, —NR′₂, —SH, —SR′, —O—C(O)R′, —C(O)R′, —CF₃, —OCF₃, an amino acidside chain or peptide fragment, where R′ is selected from radicalsconsisting of H, heteroaryl having 1 to 4 N, O and/or S atoms, C₁₋₂₀alkyl, C₁₋₂₀ alkylamino, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₄₋₁₀heterocycle, C₄₋₁₀ heteroaryl, ammonium and salts thereof, sulfates,sulfonates, thiosulfonates, boronates, phosphates, phosphonate,guanidine, amidine, pyridine, pyridium, alkali metal groups, nitrates,chlorates, perchlorates, acetates, chloride, bromide, iodide and saltsthereof, an alkali metal salt of sulfonic acid; an alkali metal salt ofphosphonic acid; a pharmaceutically acceptable salt; a sugar, apolyhydroxy group or prodrugs thereof.

In certain embodiments, a TLR8-agonist comprises:

5-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18a)

5-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18b)

5-(4-Aminobutyl)-3-pentylquinolin-2-amine (34a)

5-(5-Aminopentyl)-3-pentylquinolin-2-amine (34b)

5-(6-Aminohexyl)-3-pentylquinolin-2-amine (34c)

7-(4-Aminobutyl)-3-pentylquinolin-2-amine (36a)

7-(5-Aminopentyl)-3-pentylquinolin-2-amine (36b)

7-(6-Aminohexyl)-3-pentylquinolin-2-amine (36c)

or pharmaceutical salts thereof.

In one embodiment, compounds are synthesized by general scheme 1:

In another embodiment, compounds are synthesized by general scheme 2:

In another embodiment, compounds are synthesized by general scheme 3:

In another embodiment, compounds are synthesized by general scheme 4:

In another embodiment, compounds are synthesized by general scheme 5:

In another embodiment, compounds are synthesized by general scheme 6:

In another embodiment, compounds are synthesized by general scheme 7:

In another embodiment, one or more compounds or salts of generalFormulas (I), (II) or (III) are administered as a pharmaceuticalcomposition.

In other embodiments, a pharmaceutical composition comprises aneffective and therapeutically effective amount of one or more compoundsor salts of Formulas (I), (II) or (III).

Uses

In embodiments, one or more compounds or salts of Formulas (I), (II) or(III) are TLR8 specific agonists. Engagement of the human toll-likereceptor (hTLR)-8 by TLR8 agonists evokes a distinct cytokine profile,e.g. TNF-α, IL-6, IL-12, etc) which favors the development of Type 1helper T cells (T_(H)1). Type 1 helper (T_(H)1), but not type 2 helper(T_(H)2), cells produce interleukin (IL)-2, gamma-interferon (IFN-γ) andtumor necrosis factor-α, whereas T_(H)2, but not T_(H)1, cells expressIL-4, IL-5, IL-6, IL-10, IL-12, IL-13, etc. The different cytokinepatterns lead to different functions of the two types of T cell. Ingeneral, T_(H)2 cells are excellent helpers for B-cell antibodysecretion, particularly IgE responses. On the other hand T_(H)1 cellsinduce delayed-type hypersensitivity reactions. Most allergen- orhelminthic antigen-specific CD4⁺ human T cell clones have a T_(H)2phenotype, whereas the majority of T-cell clones specific formycobacterial antigens or antigens responsible for type IVhypersensitivity exhibit a T_(H)1 phenotype. Selective or preferentialactivation of CD4⁺ T-cell subsets secreting defined patterns ofcytokines is of major importance in determining the class of immuneeffector function, thus influencing both protection and immunopathology.

Strongly T_(H)1-biasing TLR8 agonists would be useful as candidatevaccine adjuvants for the newborn. Maternal immunoglobulins acquiredpassive transplacental passage, confer protection to the neonate for thefirst few weeks of life; thereafter, the newborn is susceptible to awide range of pathogens until early infancy. The very young do not mountadequate adaptive immune responses and, consequently, even highlyeffective vaccines that confer excellent protection in adults fail toelicit strong immune responses in them. The neonatal immunophenotype ischaracterized by decreased production of both type I and type IIinterferons, as well as T_(H)1-biasing cytokines such as TNF-α, IL-12,IL-18, IL-23, the preferential induction of memory B lymphocytes ratherthan immunoglobulin-secreting plasma cells, as well as a pronounced type2 helper (T_(H)2) skewing of T-cell responses.

Accordingly, in one preferred embodiment, one or more compounds ofFormulas (I), (II) or (III) modulate an immune response in vitro or invivo. In another preferred embodiment, one or more compounds of Formulas(I), (II) or (III) are administered as a vaccine adjuvant.

In another embodiment, a pharmaceutical composition comprising aneffective amount of one or more compounds of Formulas (I), (II) or (III)are administered to a patient in need thereof, either alone, incombination with another therapeutic agent or as part of a therapy. Thetherapeutic agent can be, for example, a vaccine, chemotherapy,radiotherapy, immuno therapy, surgery, antibiotics, anti-fungal, etc.

In another embodiment, a pharmaceutical composition comprising aneffective amount of one or more compounds of Formulas (I), (II) or(III), is administered to a patient in need thereof, as an adjuvant. Thecompounds can, for example, stimulate an immune response to a weaklyimmunogenic antigen, vaccine etc.

In some aspects, a method comprising administering any of thecompositions provided herein to a subject in an amount effective tomodulate an immune response is provided. In some embodiments, thecomposition is in an amount effective to induce or enhance an immuneresponse. In some embodiments, the composition is in an amount effectiveto suppress an immune response. In some embodiments, the composition isin an amount effective to direct or redirect an immune response. In someembodiments, the method is for prophylaxis and/or treatment of thediseases or disorders which would benefit by an enhanced immuneresponse.

In some embodiments, where the method is to induce or enhance an immuneresponse, the subject has or is susceptible to having cancer, aninfectious disease, a non-autoimmune metabolic or degenerative disease,an atopic disease, or an addiction. In some embodiments, the subject hasbeen exposed to or may be exposed to a toxin. In some embodiments, thesubject has been exposed to or may be exposed to a toxin from a chemicalweapon. In some embodiments, the method raises high titer antibodiesthat bind and neutralize the offending agent before it reaches itseffector site (e.g., the brain).

In some embodiments, the infectious disease is a chronic viralinfection. In some embodiments, the chronic viral infection is HIV, HPV,HBV, or HCV infection.

In some aspects, the compositions comprising compounds of Formulas (I),(II) or (III) are administered with immunomodulatory agents thatstimulate various cells of the immune system. For example, B cells, Tcells, antigen-presenting cells (APCs). In some preferred embodiments,the compounds induce a T_(H)1 type immune response.

In some embodiments, an immunomodulatory agent may comprise isolatedand/or recombinant proteins or peptides, vaccines, carbohydrates,glycoproteins, glycopeptides, proteoglycans, inactivated organisms andviruses, dead organisms and virus, genetically altered organisms orviruses, and cell extracts. In some embodiments, an immunomodulatoryagent may comprise nucleic acids, carbohydrates, lipids, and/or smallmolecules. In some embodiments, an immunomodulatory agent is one thatelicits an immune response. In some embodiments, an immunomodulatoryagent is an antigen. In some embodiments, an immunomodulatory agent isused as a vaccine. In some embodiments, an immunomodulatory agent is anyprotein and/or other antigen derived from a pathogen. The pathogen maybe a virus, bacterium, fungus, protozoan, parasite, etc. In someembodiments, an immunomodulatory agent may be in the form of wholekilled organisms, peptides, proteins, glycoproteins, glycopeptides,proteoglycans, carbohydrates, or combinations thereof.

Pharmaceutical Compositions

As discussed above, the invention also includes pharmaceuticalcompositions containing compounds having a general Formulas (I), (II) or(III). In some embodiments, the compositions are suitable for internaluse and include an effective amount of a pharmacologically activeconjugate of the invention, alone or in combination, with one or morepharmaceutically acceptable carriers.

The patient having pathology, e.g. the patient treated by the methods ofthis invention can be a mammal, or more particularly, a human. Inpractice, the agents are administered in amounts which will besufficient to exert their desired biological activity.

The pharmaceutical compositions of the invention may contain, forexample, more than one type of compounds of Formulas (I), (II) or (III).In some examples, a pharmaceutical composition of the invention,containing one or more compounds of the invention, is administered incombination with another useful composition such as, a vaccine,antibodies, an anti-inflammatory agent, an immunostimulator, achemotherapeutic agent, an antiviral agent, or the like. Furthermore,the compositions of the invention may be administered in combinationwith a cytotoxic, cytostatic, or chemotherapeutic agent such as analkylating agent, anti-metabolite, mitotic inhibitor or cytotoxicantibiotic. In general, the currently available dosage forms of theknown therapeutic agents for use in such combinations will be suitable.

In certain embodiments, a method of modulating an immune response invitro or in vivo, comprises contacting a cell or administering to asubject in need thereof, a composition comprising one or more compoundsof general Formulas (I), (II) or (III). Examples of such compounds,comprise:

5-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18a)

5-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18b)

5-(4-Aminobutyl)-3-pentylquinolin-2-amine (34a)

5-(5-Aminopentyl)-3-pentylquinolin-2-amine (34b)

5-(6-Aminohexyl)-3-pentylquinolin-2-amine (34c)

7-(4-Aminobutyl)-3-pentylquinolin-2-amine (36a)

7-(5-Aminopentyl)-3-pentylquinolin-2-amine (36b)

7-(6-Aminohexyl)-3-pentylquinolin-2-amine (36c)

or pharmaceutical salts thereof.

An immunomodulatory agent such as a vaccine, can be administered to thesubject before, in conjunction with, or after administration of thecomposition.

In another embodiment, a method of increasing an immune response in asubject to an immunomodulatory agent such as, for example, an antigen orvaccine, comprises administering the immunomodulatory agent to thesubject; administering a composition comprising an effective amount ofone or more compounds of general Formulas (I), (II) or (III). Thesecompounds, for example, comprise one or more of:

5-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18a)

5-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18b)

5-(4-Aminobutyl)-3-pentylquinolin-2-amine (34a)

5-(5-Aminopentyl)-3-pentylquinolin-2-amine (34b)

5-(6-Aminohexyl)-3-pentylquinolin-2-amine (34c)

7-(4-Aminobutyl)-3-pentylquinolin-2-amine (36a)

7-(5-Aminopentyl)-3-pentylquinolin-2-amine (36b)

7-(6-Aminohexyl)-3-pentylquinolin-2-amine (36c)

or pharmaceutical salts thereof.

As discussed infra, the composition comprising the one or more compoundsof general Formulas (I), (II) or (III), are pre-administered beforeadministration of the antigen or vaccine, co-administered with theantigen or vaccine, or post-administration of the antigen or vaccine.

Combination therapy (or “co-therapy”) includes the administration of thecompositions and at least a second agent as part of a specific treatmentregimen intended to provide the beneficial effect from the co-action ofthese therapeutic agents. The beneficial effect of the combinationincludes, but is not limited to, pharmacokinetic or pharmacodynamicco-action resulting from the combination of therapeutic agents.Administration of these therapeutic agents in combination typically iscarried out over a defined time period (usually minutes, hours, days orweeks depending upon the combination selected).

Combination therapy may, but generally is not, intended to encompass theadministration of two or more of these therapeutic agents as part ofseparate monotherapy regimens that incidentally and arbitrarily resultin the combinations of the present invention. Combination therapy isintended to embrace administration of compounds of Formulas (I), (II) or(III) in a sequential manner, that is, wherein each therapeutic agent isadministered at a different time, as well as administration of thesetherapeutic agents, or at least two of the therapeutic agents, in asubstantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.

Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, topical routes, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents can be administered by the same route orby different routes. For example, a first therapeutic agent of thecombination selected may be administered by injection while the othertherapeutic agents of the combination may be administered topically.

Alternatively, for example, all therapeutic agents may be administeredtopically or all therapeutic agents may be administered by injection.The sequence in which the therapeutic agents are administered is notnarrowly critical unless noted otherwise. Combination therapy also canembrace the administration of the therapeutic agents as described abovein further combination with other biologically active ingredients. Wherethe combination therapy further comprises a non-drug treatment, thenon-drug treatment may be conducted at any suitable time so long as abeneficial effect from the co-action of the combination of thetherapeutic agents and non-drug treatment is achieved. For example, inappropriate cases, the beneficial effect is still achieved when thenon-drug treatment is temporally removed from the administration of thetherapeutic agents, perhaps by days or even weeks.

Therapeutic or pharmacological compositions of the present inventionwill generally comprise an effective amount of the active component(s),dissolved or dispersed in a pharmaceutically acceptable medium.Pharmaceutically acceptable media or carriers include any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Supplementary active ingredients can also be incorporatedinto the therapeutic compositions of the present invention.

For any agent used in the methods of the invention, the therapeuticallyeffective amount or dose can be estimated initially from activity assaysin cell cultures and/or animals. For example, a dose can be formulatedin animal models to achieve a circulating concentration range thatincludes the IC₅₀ as determined by activity assays (e.g., theconcentration of the test compound, which achieves a half-maximalinhibition of the proliferation activity). Such information can be usedto more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the peptides described herein canbe determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the IC₅₀ and the LD₅₀ (lethal dose causingdeath in 50% of the tested animals) for a subject compound. The dataobtained from these activity assays and animal studies can be used informulating a range of dosage for use in human.

The dosage may vary depending upon the dosage form employed and theroute of administration utilized. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition. Dosage amount and interval may beadjusted individually to provide plasma levels of the active moietywhich are sufficient to maintain therapeutic effects, termed the minimaleffective concentration (MEC). The MEC will vary for each preparation,but can be estimated from in vitro and/or in vivo data, e.g., theconcentration necessary to achieve 50-90% inhibition of a proliferationof certain cells may be ascertained using the assays described herein.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. HPLC assays or bioassayscan be used to determine plasma concentrations. Dosage intervals canalso be determined using the MEC value. Preparations should beadministered using a regimen, which maintains plasma levels above theMEC for 10-90% of the time, preferably between 30-90% and mostpreferably 50-90%. Depending on the severity and responsiveness of thecondition to be treated, dosing can also be a single administration of aslow release composition described hereinabove, with course of treatmentlasting from several days to several weeks or until cure is effected ordiminution of the disease state is achieved. The amount of a compositionto be administered will, of course, be dependent on the subject beingtreated, the severity of the affliction, the manner of administration,the judgment of the prescribing physician, etc.

The preparation of pharmaceutical or pharmacological compositions willbe known to those of skill in the art in light of the presentdisclosure. Typically, such compositions may be prepared as injectables,either as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid prior to injection; as tablets orother solids for oral administration; as time release capsules; or inany other form currently used, including eye drops, creams, lotions,salves, inhalants and the like. The use of sterile formulations, such assaline-based washes, by surgeons, physicians or health care workers totreat a particular area in the operating field may also be particularlyuseful. Compositions may also be delivered via microdevice,microparticle or other known methods.

Upon formulation, therapeutics will be administered in a mannercompatible with the dosage formulation, and in such amount as ispharmacologically effective. The formulations are easily administered ina variety of dosage forms, such as the type of injectable solutionsdescribed above, but drug release capsules and the like can also beemployed.

In this context, the quantity of active ingredient and volume ofcomposition to be administered depends on the host animal to be treated.Precise amounts of active compound required for administration depend onthe judgment of the practitioner and are peculiar to each individual.

The pharmaceutical compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. The compositions are prepared according toconventional mixing, granulating, or coating methods, and typicallycontain about 0.1% to 75%, preferably about 1% to 50%, of the activeingredient.

Liquid, particularly injectable compositions can, for example, beprepared by dissolving, dispersing, etc. The active compound isdissolved in or mixed with a pharmaceutically pure solvent such as, forexample, water, saline, aqueous dextrose, glycerol, ethanol, and thelike, to thereby form the injectable solution or suspension.Additionally, solid forms suitable for dissolving in liquid prior toinjection can be formulated.

The compositions of the present invention can be administered inintravenous (both bolus and infusion), intraperitoneal, subcutaneous orintramuscular form, all using forms well known to those of ordinaryskill in the pharmaceutical arts. Injectables can be prepared inconventional forms, either as liquid solutions or suspensions.

Parenteral injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Additionally, oneapproach for parenteral administration employs the implantation of aslow-release or sustained-released systems, which assures that aconstant level of dosage is maintained.

Furthermore, preferred compositions for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, inhalants, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Other preferred topicalpreparations include creams, suppositories, ointments, lotions, aerosolsprays and gels, wherein the concentration of active ingredient wouldtypically range from 0.01% to 15%, w/w or w/v.

The active compound defined above, may be also formulated assuppositories, using for example, polyalkylene glycols, for example,propylene glycol, as the carrier. In some embodiments, suppositories areadvantageously prepared from fatty emulsions or suspensions.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, containing cholesterol,stearylamine or phosphatidylcholines. In some embodiments, a film oflipid components is hydrated with an aqueous solution of drug to a formlipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564. For example, the molecules described herein can be providedas a complex with a lipophilic compound or non-immunogenic, highmolecular weight compound constructed using methods known in the art. Anexample of nucleic-acid associated complexes is provided in U.S. Pat.No. 6,011,020.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

If desired, the pharmaceutical composition to be administered may alsocontain minor amounts of non-toxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents, and other substances such asfor example, sodium acetate, and triethanolamine oleate. The dosageregimen utilizing the molecules is selected in accordance with a varietyof factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated;the route of administration; the renal and hepatic function of thepatient; and the particular molecule or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition. Compounds of the presentinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily.

All documents mentioned herein are incorporated herein by reference. Allpublications and patent documents cited in this application areincorporated by reference for all purposes to the same extent as if eachindividual publication or patent document were so individually denoted.By their citation of various references in this document, Applicants donot admit any particular reference is “prior art” to their invention.

EXAMPLES

The invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention. The following non-limiting examples are illustrative of theinvention.

Example 1: Structure-Based Design of Human TLR8-Specific Agonists withAugmented Potency and Adjuvanticity

Previous work, by the inventors, on identifying small molecule agonistsof TLR8 include: 2,3-diamino-furo[2,3-c]pyridines (Salunke, D. B. et al.J. Med. Chem. 2012, 55, 8137-8151), 4-amino-furo[2,3-c]quinolines(Kokatla, H. P. et al. J. Med. Chem. 2013, 56, 6871-6885),3-alkyl-quinoline-2-amines (Kokatla, H. P. et al. Chem. Med. Chem. 2014,9, 719-723), and 1-alkyl-2-aminobenzimidazoles (Beesu, M. et al. J. Med.Chem. 2014, 57, 7325-7341), all of which are pure TLR8 agonists with nodetectable activity at TLR7.

Crystal structures of the ectodomain of human TLR8 (hTLR8)co-crystallized with two regioisomers of dual TLR7/8-agonisticN1-aminomethylbenzyl-substituted imidazoquinolines (1, 2) (Shukla, N. M.et al. J. Med. Chem. 2010, 53, 4450-4465) showed subtle differences intheir interactions in the binding site of hTLR8 (FIG. 1). TheN1-substituent of 1 was observed to H-bond with a backbone carbonylgroup, while in 2, a stronger salt-bridge was present, which fullyexplained the higher TLR8 activity of 2. The questions addressed hereinwere whether the TLR8-agonistic potency of the best-in-class compound ofthe 3-alkyl-quinoline-2-amine series could be further enhanced by‘designing in’ functional groups which would mimic the ionic H-bondobserved in the hTLR8/2 complex.

A focused and hypothesis-driven exploration of introducing alkylaminogroups at all possible positions on the quinoline core is reportedherein. These studies led to the identification of a novel TLR8 agonistwhich was ˜20-fold more potent than the parent compound.

Materials and Methods

Abbreviations: APCs, Antigen-presenting cells; CD, Cluster ofdifferentiation; EC50, Half-maximal effective concentration; ESI-TOF,Electrospray ionization-time of flight; HEK, Human embryonic kidney;IFN, Interferon; IL, Interleukin; MHC, Major histocompatibility complex;MPL®, monophosphoryl lipid A; NF-κB, Nuclear factor-κB; NK, Naturalkiller; NLR, Nod-like receptor; NOD-1 and -2, Nucleotide-bindingoligomerization domain-containing protein 1 and 2; PBMCs, Peripheralblood mononuclear cells; sAP, Secreted alkaline phosphatase; Th1, HelperT lymphocyte, type 1; Th2, Helper T lymphocyte, type 2; TLR, Toll-likereceptor; TNF-α, Tumor necrosis factor-α.

Chemistry: All of the solvents and reagents used were obtainedcommercially and used as such unless noted otherwise. Moisture- orair-sensitive reactions were conducted under nitrogen atmosphere inoven-dried (120° C.) glass apparatus. Solvents were removed underreduced pressure using standard rotary evaporators. Flash columnchromatography was carried out using RediSep Rf ‘Gold’ high performancesilica columns on CombiFlash Rf instruments unless otherwise mentioned,while thin-layer chromatography was carried out on silica gel CCMpre-coated aluminum sheets. Purity for all final compounds was confirmedto be greater than 98% by LC-MS using a Zorbax Eclipse Plus 4.6 mm×150mm, 5 μm analytical reverse phase C₁₈ column with H₂O—CH₃CN and H₂O-MeOHgradients and an Agilent 6520 ESI-QTOF Accurate Mass spectrometer (massaccuracy of 5 ppm) operating in the positive ion acquisition mode.Compound 4 was synthesized as previously described (Kokatla, H. P. Chem.Med. Chem. 2014, 9, 719-723).

3-((3-(Pent-1-yn-1-yl)quinolin-4-yl)methyl)benzonitrile (5a). To asolution of compound 4 (230 mg, 1 mmol) in DMF (5 mL) were added3-cyanobenzylzinc bromide (4 mL, 2 mmol, 0.5 M in THF) and LiCl (85 mg,2 mmol). The resulting reaction mixture was stirred for 24 h at roomtemperature under nitrogen atmosphere. The reaction mixture was dilutedwith water and extracted with EtOAc (3×30 mL). The combined organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (40% EtOAc/hexanes)to obtain the compound 5a as a pale yellow solid (179 mg, 58%). ¹H NMR(500 MHz, CDCl₃) δ 8.93 (s, 1H), 8.10 (dd, J=1.2, 8.4 Hz, 1H), 7.87 (dd,J=1.3, 8.3 Hz, 1H), 7.67 (ddd, J=1.3, 6.9, 8.4 Hz, 1H), 7.55-7.50 (m,2H), 7.49-7.46 (m, 1H), 7.44-7.41 (m, 1H), 7.34 (t, J=7.7 Hz, 1H), 4.65(s, 2H), 2.47 (t, J=7.0 Hz, 2H), 1.73-1.52 (m, 2H), 1.02 (t, J=7.4 Hz,3H). 13C NMR (126 MHz, CDCl₃) δ 152.89, 147.08, 145.67, 140.55, 132.90,132.02, 130.52, 130.36, 129.55, 129.51, 127.65, 126.62, 123.91, 119.01,118.90, 112.77, 98.31, 77.53, 35.56, 22.20, 21.80, 13.70. MS (ESI-TOF)for C₂₂H₁₈N₂[M+H]+ calculated 311.1543, found 311.1441.

Compound 5b was synthesized similarly as compound 5a.

4-((3-(Pent-1-yn-1-yl)quinolin-4-yl)methyl)benzonitrile (5b).4-Cyanobenzylzinc bromide was used as reagent. Pale yellow solid (201mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 8.93 (s, 1H), 8.09 (dd, J=0.8, 8.4Hz, 1H), 7.84 (dd, J=0.8, 8.5 Hz, 1H), 7.67 (ddd, J=1.4, 6.9, 8.4 Hz,1H), 7.56-7.48 (m, 3H), 7.32-7.26 (m, 2H), 4.69 (s, 2H), 2.46 (t, J=7.0Hz, 2H), 1.74-1.51 (m, 2H), 1.01 (t, J=7.4 Hz, 3H). ¹³C NMR (126 MHz,CDCl3) δ 152.87, 147.07, 145.59, 144.64, 132.54, 130.50, 129.55, 129.18,127.61, 126.68, 123.97, 119.08, 118.94, 110.49, 98.24, 77.50, 36.17,22.19, 21.79, 13.69. MS (ESI-TOF) for C₂₂H₁₈N₂ [M+H]⁺ calculated311.1543, found 311.1504.

4-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine dihydrochloride (9a).A solution of compound 5a (155 mg, 0.5 mmol) in THE (5 mL) was addedslowly to a solution of LiAlH₄ (2.5 mL, 2.5 mmol, 1.0 M in THF) in THE(5 mL) at 0° C. under nitrogen atmosphere. The reaction mixture wasstirred for 1 h at 25° C. and 5 h at 75° C. The reaction mixture wascooled to room temperature and quenched carefully with ice-cold water.The resulting mixture was basified with 10% NaOH (to pH=8.0) andextracted with CH₂Cl₂ (3×30 mL). The combined organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain theresidue. The residue was dissolved in MeOH and di-t-butyl dicarbamate(109 mg, 0.5 mmol) was added and stirred under nitrogen for 1 h. Thesolvent was removed under vacuum. The resulting residue was purified byflash chromatography (20% EtOAc/hexanes) to obtain the compound 6a as apale yellow solid (134 mg, 65%). MS (ESI-TOF) for C₂₇H₃₀N₂O₂ [M+H]⁺calculated 415.2380, found 415.2266. To a stirred solution of substrate6a (124 mg, 0.3 mmol) in CHCl₃ was added m-CPBA (134 mg, 0.6 mmol). Theresulting reaction mixture was stirred for 4 h at room temperature. Thereaction mixture was diluted with water and extracted with CH₂Cl₂ (3×20mL). The combined organic layer was dried over Na₂SO₄, concentratedunder reduced pressure, and the crude material was purified by flashchromatography (10% MeOH/CH₂Cl₂) to obtain 7a as a yellow solid (98 mg,76%). MS (ESI-TOF) for C₂₇H₃₀N₂O₃ [M+H]⁺ calculated 431.2329, found431.2122. To a stirred solution of 7a (86 mg, 0.2 mmol) in CH₂Cl₂ wasadded benzoyl isocyanate (88 mg, 0.6 mmol). The resulting reactionmixture was stirred at 55° C. for 1 h. After completion of reaction(monitored by TLC), the solvent was removed under reduced pressure. Theresidue was re-dissolved in MeOH (5 mL), NaOMe (54 mg, 1 mmol) was addedand refluxed for 2 h. The solvent was removed and the crude material waspurified by flash chromatography (10% MeOH/CH₂Cl₂) to obtain 8a as anoff-white solid (67 mg, 78%). MS (ESI-TOF) for C₂₇H₃₁N₃O₂ [M+H]⁺calculated 430.2489, found 430.2303. To a solution of compound 8a (43mg, 0.1 mmol) in anhydrous EtOAc (10 mL) was added a catalytic amount ofPt/C, and the reaction mixture was subjected to hydrogenation at 30 psifor 30 min. The reaction mixture was filtered, and the filtrateconcentrated under reduced pressure. The crude material was purified byflash chromatography (10% MeOH/CH₂Cl₂) to obtain N-Boc protectedbenzylamine as a white solid (32 mg). MS (ESI-TOF) for C₂₇H₃₅N₃O₂ [M+H]⁺calculated 434.2802, found 434.2612. To a stirred solution of N-Bocprotected benzylamine (32 mg) in 1,4-dioxane (1 mL) was added hydrogenchloride (1 mL, 4 M in dioxane), and the reaction mixture was stirredfor 1 h at room temperature. Excess solvent was removed under reducedpressure and the resulted residue was thoroughly washed with diethylether to obtain the desired compound 9a as a white solid (28 mg, 69%).1H NMR (500 MHz, MeOD) δ 7.97-7.91 (m, 1H), 7.77-7.64 (m, 2H), 7.43(ddd, Jr 1.4, 7.0, 8.4 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.36-7.31 (m,1H), 7.28 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 4.62 (s, 2H), 4.06 (s, 2H),2.81 (t, J=8.5 Hz, 2H), 1.58-1.49 (m, 2H), 1.47-1.39 (m, 2H), 1.36-1.25(m, 2H), 0.89 (t, J=7.3 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 155.07,151.34, 140.27, 136.23, 135.28, 133.06, 130.87, 129.87, 129.62, 128.43,127.13, 126.67, 126.32, 123.05, 118.59, 44.08, 34.87, 32.75, 29.22,28.11, 23.67, 14.34. MS (ESI-TOF) for C₂₂H₂₇N₃[M+H]⁺ calculated334.2278, found 334.2238.

Compound 9b was synthesized similarly as compound 9a.

4-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine dihydrochloride (9b).White solid (30 mg, 74%). ¹H NMR (500 MHz, MeOD) δ 7.91 (dd, J=1.2, 8.4Hz, 1H), 7.79-7.64 (m, 2H), 7.44-7.37 (m, 3H), 7.22 (d, J=8.0 Hz, 2H),4.62 (s, 2H), 4.07 (s, 2H), 2.79 (t, J=8.2 Hz, 2H), 1.57-1.47 (m, 2H),1.46-1.38 (m, 2H), 1.36-1.27 (m, 2H), 0.89 (t, J=7.3 Hz, 3H). 13C NMR(126 MHz, MeOD) δ 155.04, 151.56, 140.37, 136.15, 133.09, 133.07,130.67, 129.85, 127.14, 126.60, 126.20, 123.00, 118.56, 43.87, 34.72,32.71, 29.19, 27.99, 23.62, 14.33. MS (ESI-TOF) for C₂₂H₂₇N₃[M+H]⁺calculated 334.2278, found 334.2257.

4-(3-(Pent-1-yn-1-yl)quinolin-4-yl)butanenitrile (10a). To a solution ofcompound 4 (229.7 mg, 1 mmol) in THF (4 mL) were added 3-cyanopropylzincbromide (4 mL, 2 mmol, 0.5 M in THF) and Pd(PPh₃)₄ (115.5 mg, 0.1 mmol).The resulting reaction mixture was stirred for 12 h at 65° C. undernitrogen atmosphere. The reaction mixture was diluted with water andextracted with EtOAc (3×30 mL). The combined organic layer was driedover Na₂SO₄ and concentrated under reduced pressure. The crude materialwas purified by flash chromatography (20% EtOAc/hexanes) to obtain thecompound 10a as a pale yellow oil (144 mg, 55%). ¹H NMR (500 MHz, CDCl₃)δ 8.84 (s, 1H), 8.11-8.06 (m, 1H), 7.98 (dd, J=1.0, 8.9 Hz, 1H), 7.69(ddd, J=1.3, 6.8, 8.3 Hz, 1H), 7.59 (ddd, J=1.3, 6.8, 8.3 Hz, 1H), 3.42(t, J=7.7 Hz, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.46 (t, J=7.0 Hz, 2H),2.14-2.03 (m, 2H), 1.77-1.62 (m, 2H), 1.10 (t, J=7.4 Hz, 3H). 13C NMR(126 MHz, CDCl₃) δ 152.74, 147.14, 146.93, 130.56, 129.49, 127.51,126.37, 123.25, 119.48, 118.15, 98.32, 77.10, 28.90, 25.79, 22.27,21.83, 17.31, 13.81. MS (ESI-TOF) for C₁₈H₁₈N₂[M+H]⁺ calculated263.1543, found 263.1437.

Compound 10b was synthesized similarly as compound 10a.

5-(3-(Pent-1-yn-1-yl)quinolin-4-yl)pentanenitrile (10b).4-Cyanobutylzinc bromide was used as reagent. Pale yellow oil (174 mg,63%). ¹H NMR (500 MHz, CDCl₃) δ 8.83 (s, 1H), 8.07 (dd, J=0.8, 8.5 Hz,11H), 7.97 (dd, J=1.0, 8.5 Hz, 1H), 7.67 (ddd, J=1.4, 6.9, 8.3 Hz, 1H),7.57 (ddd, J=1.3, 6.9, 8.3 Hz, 1H), 3.30 (t, J=7.5 Hz, 2H), 2.51 (t,J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 1.95-1.84 (m, 2H), 1.85-1.75 (m,2H), 1.76-1.65 (m, 2H), 1.10 (t, J=7.4 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃)δ 152.78, 148.54, 146.91, 130.45, 129.34, 127.22, 126.48, 123.54,119.52, 117.88, 97.62, 77.51, 29.32, 29.02, 25.41, 22.33, 21.81, 17.20,13.79. MS (ESI-TOF) for C₁₉H₂₀N₂[M+H]⁺ calculated 277.1699, found277.1581.

Compounds 14a and 14b were synthesized similarly as compound 9a.

4-(4-Aminobutyl)-3-pentylquinolin-2-amine dihydrochloride (14a). Whitesolid (28 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.11 (d, J=8.1 Hz, 1H),7.76 (ddd, J=1.2, 7.1, 8.4 Hz, 1H), 7.67 (dd, J=1.2, 8.4 Hz, 1H), 7.57(ddd, J=1.2, 7.1, 8.3 Hz, 11H), 3.19 (t, J=8.2 Hz, 2H), 3.01 (t, J=7.6Hz, 2H), 2.80 (t, J=8.2 Hz, 2H), 1.98-1.87 (m, 2H), 1.80-1.70 (m, 2H),1.65-1.55 (m, 2H), 1.56-1.46 (m, 2H), 1.47-1.38 (m, 2H), 0.96 (t, J=7.2Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 154.80, 154.01, 135.98, 133.05,126.77, 126.45, 124.51, 122.47, 118.61, 40.50, 32.81, 29.52, 29.45,28.86, 28.16, 27.56, 23.73, 14.42. MS (ESI-TOF) for C₁₈H₂₇N₃[M+H]⁺calculated 286.2278, found 286.2240.

4-(5-Aminopentyl)-3-pentylquinolin-2-amine dihydrochloride (14b). Whitesolid (29 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.09 (d, J=8.2 Hz, 1H),7.76 (ddd, J=1.2, 7.0, 8.3 Hz, 1H), 7.66 (d, J=7.6 Hz, 11H), 7.56 (ddd,J=1.2, 7.0, 8.3 Hz, 1H), 3.16 (t, J=6.7 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H),2.79 (t, J=8.4 Hz, 2H), 1.80-1.64 (m, 6H), 1.64-1.56 (m, 2H), 1.54-1.46(m, 2H), 1.48-1.38 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). ¹³C NMR (126 MHz,MeOD) δ 154.78, 154.54, 135.97, 133.00, 126.70, 126.41, 124.30, 122.51,118.60, 40.61, 32.81, 30.92, 29.79, 29.52, 28.48, 27.85, 27.54, 23.73,14.41. MS (ESI-TOF) for C₁₉H₂₉N₃[M+H]⁺ calculated 300.2434, found300.2397.

5-Bromo-3-pentylquinolin-2-amine (16). To a solution of compound 15 (200mg, 1 mmol) in DMSO (3 mL) were added heptanenitrile (275 μL, 2 mmol)and t-BuOK (224 mg, 2 mmol). The resulting reaction mixture was stirredfor 3 h at 60° C. under nitrogen atmosphere. The reaction mixture wasdiluted with water and extracted with EtOAc (3×50 mL). The combinedorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by flash chromatography (50%EtOAc/hexanes) to obtain the compound 16 as a off-white solid (220 mg,75%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.49-7.40 (m, 2H), 7.34(dd, J=7.6, 8.3 Hz, 1H), 6.58 (s, 2H), 2.62 (t, J=7.8 Hz, 2H), 1.66-1.57(m, 2H), 1.44-1.29 (m, 4H), 0.89 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz,DMSO-d₆) δ 157.75, 147.59, 132.61, 128.85, 126.08, 124.89, 124.73,121.98, 120.40, 30.96, 30.29, 27.42, 22.06, 14.01. MS (ESI-TOF) forC₁₄H₁₇BrN₂ [M+H]⁺ calculated 293.0648, found 293.0684.

3-((2-Amino-3-pentylquinolin-5-yl)methyl)benzonitrile (17a). To asolution of compound 16 (58.8 mg, 0.2 mmol) in THE (2 mL) were added3-cyanobenzylzinc bromide (0.8 mL, 0.4 mmol, 0.5 M in THF) and Pd(PPh₃)₄(11.6 mg, 0.01 mmol). The resulting reaction mixture was stirred at 65°C. under nitrogen atmosphere for 12 h. The reaction mixture was dilutedwith water and extracted with EtOAc (3×10 mL). The combined organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (60% EtOAc/hexanes)to obtain the compound 17a as a pale yellow solid (54 mg, 82%). ¹H NMR(500 MHz, CDCl₃) δ 7.67 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.51-7.44 (m,3H), 7.40-7.33 (m, 2H), 7.07 (d, J=7.0 Hz, 1H), 4.80 (s, 2H), 4.37 (s,2H), 2.52 (t, J=7.6 Hz, 2H), 1.66-1.56 (m, 2H), 1.38-1.21 (m, 4H), 0.88(t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.95, 147.28, 142.44,134.55, 133.17, 132.16, 131.77, 130.13, 129.40, 128.69, 125.59, 124.49,123.66, 122.91, 119.00, 112.68, 38.40, 31.52, 31.49, 27.56, 22.63,14.15. MS (ESI-TOF) for C₂₂H₂₃N₃[M+H]⁺ calculated 330.1965, found330.1896.

Compounds 17b-d were synthesized similarly as compound 17a.

4-((2-Amino-3-pentylquinolin-5-yl)methyl)benzonitrile (17b).4-Cyanobenzylzinc bromide was used as reagent. Pale yellow solid (55 mg,83%). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.62 (d, J=8.5 Hz, 1H),7.56 (d, J=8.3 Hz, 2H), 7.48 (dd, J=7.0, 8.4 Hz, 1H), 7.30-7.25 (m, 2H),7.09 (d, J=6.8 Hz, 1H), 4.81 (s, 2H), 4.41 (s, 2H), 2.52 (t, J=7.8 Hz,2H), 1.66-1.53 (m, 2H), 1.39-1.19 (m, 4H), 0.89 (t, J=7.1 Hz, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 155.95, 147.26, 146.62, 134.50, 132.44, 131.82,129.42, 128.68, 125.56, 124.54, 123.63, 122.96, 119.07, 110.20, 39.00,31.51, 31.45, 27.53, 22.63, 14.15. MS (ESI-TOF) for C₂₂H23N₃ [M+H]⁺calculated 330.1965, found 330.1899.

2-((2-Amino-3-pentylquinolin-5-yl)methyl)benzonitrile (17c).2-Cyanobenzylzinc bromide was used as reagent. Pale yellow solid (45 mg,68%). ¹H NMR (500 MHz, CDCl₃) δ 7.71 (s, 1H), 7.69 (dd, J=1.1, 7.7 Hz,1H), 7.61 (d, J=8.5 Hz, 1H), 7.47 (dd, J=7.1, 8.5 Hz, 1H), 7.39 (td,J=1.4, 7.7 Hz, 1H), 7.29 (td, J=1.2, 7.6 Hz, 1H), 7.07 (dd, J=1.1, 7.1Hz, 1H), 7.00 (dd, J=0.6, 7.9 Hz, 1H), 4.81 (s, 2H), 4.57 (s, 2H), 2.53(t, J=7.6 Hz, 2H), 1.67-1.60 (m, 2H), 1.38-1.22 (m, 4H), 0.87 (t, J=7.1Hz, 3H). ¹³C NMR (126 MHz, CDCl3) δ 156.01, 147.18, 144.65, 134.08,133.05, 132.87, 131.83, 129.79, 128.64, 126.92, 125.57, 124.59, 123.80,123.06, 118.25, 112.43, 36.89, 31.56, 31.48, 27.55, 22.62, 14.16. MS(ESI-TOF) for C₂₂H₂₃N₃[M+H]⁺ calculated 330.1965, found 330.2008.

5-Benzyl-3-pentylquinolin-2-amine (17d). Benzylzinc bromide was used asreagent. White solid (50 mg, 82%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (s,1H), 7.41-7.31 (m, 2H), 7.28-7.18 (m, 4H), 7.18-7.11 (m, 1H), 7.05-7.00(m, 1H), 6.21 (s, 2H), 4.28 (s, 2H), 2.55-2.49 (m, 2H), 1.57-1.47 (m,2H), 1.32-1.17 (m, 4H), 0.83 (t, J=7.2 Hz, 3H). ¹³C NMR (126 MHz,DMSO-d₆) δ 156.73, 147.10, 141.09, 136.57, 131.20, 128.43, 128.28,127.75, 125.84, 123.78, 123.50, 122.48, 121.73, 37.77, 30.72, 30.31,27.23, 22.06, 13.96. MS (ESI-TOF) for C₂₁H₂₄N₂[M+H]⁺ calculated305.2012, found 305.1951.

5-(3-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18a). A solution ofcompound 17a (33 mg, 0.1 mmol) in THF (5 mL) was added slowly to asolution of LiAlH₄ (0.5 mL, 0.5 mmol, 1.0 M in THF) in THF (3 mL) at 0°C. under nitrogen atmosphere. The reaction mixture was stirred for 2 hat 25° C. and 2 h at 75° C. The reaction mixture was carefully quenchedwith ice-cold water (1 mL) at 0° C. and 10% NaOH (1 mL) was added. Theresulting mixture was stirred for 10 min at room temperature, filteredthrough celite and washed with CH₂Cl₂ (15 mL). The resulting filtratewas dried over Na₂SO₄ and concentrated under reduced pressure and thecrude material was purified by neutral-alumina column chromatography(20% MeOH/CH₂Cl₂) to obtain the compound 18a as a white solid (24 mg,72%). ¹H NMR (500 MHz, MeOD) δ 7.88 (s, 1H), 7.46-7.38 (m, 2H), 7.21 (t,J=7.5 Hz, 1H), 7.18-7.10 (m, 3H), 7.06 (d, J=7.4 Hz, 1H), 4.34 (s, 2H),3.70 (s, 2H), 2.55 (t, J=7.5 Hz, 2H), 1.60 (p, J=7.6 Hz, 2H), 1.42-1.20(m, 4H), 0.89 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 158.00,147.60, 143.84, 142.65, 138.04, 133.82, 129.68, 129.58, 128.69, 128.24,126.21, 125.12, 125.06, 124.29, 123.67, 46.67, 39.64, 32.47, 31.77,28.68, 23.64, 14.41. MS (ESI-TOF) for C₂₂H₂₇N₃[M+H]⁺ calculated334.2278, found 334.2214.

Compounds 18b and 18c were synthesized similarly as compound 18a.

5-(4-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18b). Compound 17bwas used as reagent. White solid (25 mg, 75%). ¹H NMR (500 MHz, MeOD) δ7.87 (s, 1H), 7.51-7.37 (m, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 7.12-7.09 (m, 1H), 4.32 (s, 2H), 3.72 (s, 2H), 2.54 (t, J=7.6Hz, 2H), 1.68-1.48 (m, 2H), 1.40-1.21 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).¹³C NMR (126 MHz, MeOD) δ 158.00, 147.60, 141.33, 141.04, 138.13,133.81, 129.74, 129.56, 128.59, 125.10, 124.98, 124.27, 123.63, 46.35,39.28, 32.48, 31.78, 28.66, 23.64, 14.41. MS (ESI-TOF) forC₂₂H₂₇N₃[M+H]⁺ calculated 334.2278, found 334.2191.

5-(2-(Aminomethyl)benzyl)-3-pentylquinolin-2-amine (18c). Compound 17cwas used as reagent. White solid (21 mg, 63%). ¹H NMR (500 MHz, MeOD) δ7.90 (s, 1H), 7.47-7.33 (m, 3H), 7.24 (td, J=1.3, 7.5 Hz, 1H), 7.15 (td,J=1.4, 7.5 Hz, 1H), 6.93 (dd, J=1.3, 7.7 Hz, 1H), 6.84 (dd, J=1.1, 7.1Hz, 1H), 4.42 (s, 2H), 3.84 (s, 2H), 2.59 (t, J=7.8 Hz, 2H), 1.68-1.57(m, 2H), 1.40-1.27 (m, 4H), 0.90 (t, J=7.1 Hz, 3H). 3C NMR (126 MHz,MeOD) δ 158.12, 147.46, 141.29, 139.25, 137.80, 133.50, 131.09, 129.58,129.13, 128.27, 127.89, 125.42, 124.27, 124.19, 123.78, 43.84, 35.93,32.58, 31.94, 28.87, 23.65, 14.42. MS (ESI-TOF) for C₂₂H₂₇N₃[M+H]⁺calculated 334.2278, found 334.2195.

3-((2-Amino-3-pentylquinolin-5-yl)methyl)benzamide (18d). To a solutionof compound 17a (33 mg, 0.1 mmol) in t-BuOH (2 mL) was added potassiumhydroxide (84 mg, 1.5 mmol). The reaction mixture was stirred for 8 h at60° C. The reaction was allowed to cool to room temperature, the solventwas removed under reduced pressure and the crude solubilized in ethylacetate. The organic layer was washed with water and saturated aqueousammonium chloride, and dried over Na₂SO₄ and evaporated under reducedpressure. The residue was purified by silica gel flash-columnchromatography (15% MeOH/CH₂Cl₂) to afford the compound (18d) as a whitesolid (18 mg, 52%). ¹H NMR (500 MHz, MeOD) δ 7.88 (s, 1H), 7.78 (d,J=0.8 Hz, 1H), 7.68 (dt, J=1.9, 7.0 Hz, 1H), 7.49-7.43 (m, 2H),7.38-7.27 (m, 2H), 7.16 (dd, J=3.2, 5.0 Hz, 1H), 4.42 (s, 2H), 2.56 (t,J=7.1 Hz, 2H), 1.58 (p, J=7.5 Hz, 2H), 1.36-1.27 (m, 2H), 1.28-1.19 (m,2H), 0.86 (t, J=7.2 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 172.26, 157.87,147.04, 142.96, 137.61, 135.13, 134.03, 133.11, 129.84, 129.66, 128.98,126.42, 125.39, 125.32, 124.08, 123.44, 39.47, 32.39, 31.68, 28.61,23.59, 14.39. MS (ESI-TOF) for C₂₂H₂₅N30 [M+H]⁺ calculated 348.2070,found 348.2022.

3-(2-Amino-3-pentylquinolin-5-yl)benzonitrile (19a). To a stirredsolution of compound 16 (59 mg, 0.2 mmol) in 1,4-dioxane (2 mL) wereadded 3-cyanophenylboronic acid (44 mg, 0.3 mmol), Pd(dppf)Cl₂ (14.6 mg,0.02 mmol), and K₂CO₃ (83 mg, 0.6 mmol). The resulting reaction mixturewas stirred for 12 h at 90° C. under nitrogen atmosphere. The reactionmixture was diluted with water and extracted with EtOAc (3×20 mL). Thecombined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure, and crude material was purified by flashchromatography (60% EtOAc/hexanes) to obtain the compound 19a as abrownish solid (40 mg, 63%). ¹H NMR (500 MHz, CDCl₃) δ 7.77-7.66 (m,4H), 7.64-7.52 (m, 3H), 7.15 (dd, J=1.2, 7.1 Hz, 1H), 4.89 (s, 2H), 2.53(t, J=7.6 Hz, 2H), 1.67-1.57 (m, 2H), 1.39-1.31 (m, 4H), 0.89 (t, J=6.9Hz, 3H). ¹³C NMR (126 MHz, CDCl3) δ 156.25, 146.96, 141.74, 137.22,134.46, 133.42, 132.79, 131.10, 129.35, 128.42, 126.31, 124.37, 123.92,122.25, 118.90, 112.78, 31.69, 31.59, 27.74, 22.57, 14.15. MS (ESI-TOF)for C₂₁H₂₁N₃[M+H]⁺ calculated 316.1808, found 316.1823.

Compound 19b was synthesized similarly as compound 19a.

4-(2-Amino-3-pentylquinolin-5-yl)benzonitrile (19b).4-Cyanophenylboronic acid was used as reagent. Brownish solid (38 mg,60%). ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.76 (m, 2H), 7.71 (d, Jr 8.4 Hz,1H), 7.61 (s, 1H), 7.60-7.53 (m, 3H), 7.17 (dd, J=1.2, 7.2 Hz, 1H), 4.89(s, 2H), 2.52 (t, J=7.7 Hz, 2H), 1.67-1.55 (m, 2H), 1.40-1.31 (m, 4H),0.89 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.24, 146.97,145.32, 137.73, 132.84, 132.32, 130.78, 128.40, 126.40, 124.35, 123.80,122.09, 119.04, 111.30, 31.68, 31.56, 27.73, 22.57, 14.16. MS (ESI-TOF)for C₂₁H₂₁N₃[M+H]⁺ calculated 316.1808, found 316.1845.

Compounds 20a-b were synthesized similarly as compound 18a.

5-(3-(Aminomethyl)phenyl)-3-pentylquinolin-2-amine (20a). Compound 19awas used as reagent. White solid (21 mg, 66%). ¹H NMR (500 MHz, MeOD) δ7.73 (s, 1H), 7.58-7.39 (m, 5H), 7.30 (d, J=6.7 Hz, 1H), 7.16 (d, J=6.6Hz, 1H), 3.88 (s, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.68-1.53 (m, 2H),1.38-1.29 (m, 4H), 0.90 (t, J=6.7 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ158.28, 147.40, 144.04, 141.73, 141.28, 134.86, 130.00, 129.55, 129.53,129.41, 127.59, 125.60, 124.69, 124.34, 123.07, 46.69, 32.56, 31.81,28.73, 23.59, 14.39. MS (ESI-TOF) for C₂₁H₂₅N₃[M+H]⁺ calculated320.2121, found 320.2072.

5-(4-(Aminomethyl)phenyl)-3-pentylquinolin-2-amine (20b). Compound 19bwas used as reagent. White solid (20 mg, 63%). ¹H NMR (500 MHz, MeOD) δ7.72 (s, 1H), 7.57-7.45 (m, 4H), 7.39 (d, J=8.1 Hz, 2H), 7.13 (dd,J=1.7, 6.6 Hz, 1H), 3.89 (s, 2H), 2.54 (t, J=7.6 Hz, 2H), 1.67-1.51 (m,2H), 1.38-1.26 (m, 4H), 0.89 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, MeOD)δ 158.26, 147.42, 142.97, 141.07, 140.07, 134.82, 131.06, 129.43,128.56, 125.58, 124.65, 124.33, 123.07, 46.45, 32.58, 31.88, 28.78,23.57, 14.40. MS (ESI-TOF) for C₂₁H₂₅N₃[M+H]+ calculated 320.2121, found320.2073.

5-(3-Aminopropyl)-3-pentylquinolin-2-amine (23). A solution of 16 (147mg, 0.5 mmol) and acrylonitrile (66 μL, 1 mmol) in DMF (4 mL) wastreated with Pd(OAc)₂ (11.2 mg, 0.05 mmol), PPh₃ (26.2 mg, 0.1 mmol) andK₂CO₃ (138 mg, 1 mmol). The resulting reaction mixture was stirred for12 h at 110° C. under nitrogen atmosphere. The reaction mixture wasdiluted with water and extracted with EtOAc (3×20 mL). The combinedorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by flash chromatography (60%EtOAc/hexanes) to obtain the compound 21 as a pale yellow solid (73 mg,55%). MS (ESI-TOF) for C₁₇H₁₉N₃[M+H]⁺ calculated 266.1652, found266.1663. To a solution of compound 21 (53 mg, 0.2 mmol) in anhydrousEtOAc (10 mL) was added a catalytic amount of Pt/C, and the reactionmixture was subjected to hydrogenation at 30 psi for 3 h. The reactionmixture was filtered, and the filtrate concentrated under reducedpressure. The crude material was purified using silica gel columnchromatography (60% EtOAc/hexanes) to obtain compound 22 as white solid(40 mg, 75%). MS (ESI-TOF) for C₁₇H₂₁N₃[M+H]⁺ calculated 268.1808, found268.1821. A solution of compound 22 (27 mg, 0.1 mmol) in THF (5 mL) wasadded slowly to a solution of LiAlH₄ (0.5 mL, 0.5 mmol, 1.0 M in THF) inTHF (3 mL) at 0° C. under nitrogen atmosphere. The reaction mixture wasstirred for 2 h at 25° C. and 2 h at 60° C. The reaction mixture wascarefully quenched with ice-cold water (1 mL) at 0° C. and 10% NaOH (1mL) was added. The resulting mixture was stirred for 10 min at roomtemperature, filtered through celite and washed with CH₂Cl₂ (15 mL). Theresulting filtrate was dried over Na₂SO₄ and concentrated under reducedpressure and the crude material was purified by flash neutral-aluminacolumn chromatography (20% MeOH/CH₂Cl₂) to obtain the compound 23 as awhite solid (15 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 7.99 (s, 1H),7.40-7.37 (m, 2H), 7.09 (dd, J=2.8, 5.4 Hz, 11H), 3.02 (t, J=7.5 Hz,2H), 2.73 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.92-1.80 (m, 2H),1.78-1.68 (m, 2H), 1.48-1.40 (m, 4H), 0.95 (t, J=7.1 Hz, 3H). ¹³C NMR(126 MHz, MeOD) δ 158.00, 147.49, 139.44, 133.35, 129.58, 125.36,123.72, 123.66, 123.41, 42.35, 35.26, 32.80, 32.15, 30.76, 29.17, 23.69,14.46. MS (ESI-TOF) for C₁₇H₂₅N₃[M+H]⁺ calculated 272.2121, found272.2155.

Compounds 27-29 were synthesized similarly as compound 16.

6-Bromo-3-pentylquinolin-2-amine (27). Compound 24 was used as reagent.White solid (230 mg, 78%). ¹H NMR (500 MHz, CDCl₃) δ 7.74 (d, J=2.2 Hz,1H), 7.58 (s, 11H), 7.56 (dd, J=2.2, 8.9 Hz, 11H), 7.51 (d, J=8.8 Hz,11H), 4.87 (s, 2H), 2.57 (t, J=7.7 Hz, 2H), 1.78-1.66 (m, 2H), 1.45-1.36(m, 4H), 0.93 (t, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 156.49,145.21, 134.44, 132.05, 129.08, 127.43, 125.84, 124.79, 115.57, 31.76,31.24, 27.56, 22.67, 14.17. MS (ESI-TOF) for C₁₄H₁₇BrN₂ [M+H]⁺calculated 293.0648, found 293.0654.

7-Bromo-3-pentylquinolin-2-amine (28). Compound 25 was used as reagent.Yellow solid (220 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 7.81 (d, J=2.2 Hz,1H), 7.63 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.32 (dd, J=1.9, 8.5 Hz, 1H),4.93 (s, 2H), 2.55 (t, J=7.9 Hz, 2H), 1.76-1.67 (m, 2H), 1.44-1.36 (m,4H), 0.93 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.88, 147.41,135.17, 128.30, 128.09, 125.98, 124.16, 123.19, 122.73, 31.79, 31.24,27.56, 22.67, 14.17. MS (ESI-TOF) for C₁₄H₁₇BrN₂ [M+H]⁺ calculated293.0648, found 293.0669.

8-Bromo-3-pentylquinolin-2-amine (29). Compound 26 was used as reagent.Pale yellow solid (250 mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ 7.82 (dd,J=1.4, 7.5 Hz, 11H), 7.65 (s, 11H), 7.55 (dd, J=1.4, 7.9 Hz, 1H), 7.08(t, J=7.7 Hz, 1H), 5.04 (s, 2H), 2.58 (t, J=7.5 Hz, 2H), 1.78-1.65 (m,2H), 1.48-1.30 (m, 4H), 0.92 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃)δ 157.09, 143.79, 135.84, 132.41, 126.93, 125.67, 124.65, 122.94,120.61, 31.76, 31.08, 27.58, 22.67, 14.16. MS (ESI-TOF) for C₁₄H₁₇BrN₂[M+H]⁺ calculated 293.0648, found 293.0675.

Compounds 30a-c, 31a-c, 32a-c and 33 were synthesized similarly ascompound 17a.

4-(2-Amino-3-pentylquinolin-5-yl)butanenitrile (30a). Compound 16 and3-cyanopropylzinc bromide were used as reagents. White solid (44 mg,78%). ¹H NMR (500 MHz, CDCl₃) δ 7.86 (s, 1H), 7.56 (d, J=8.4 Hz, 1H),7.44 (dd, J=7.1, 8.4 Hz, 1H), 7.10 (dd, J=1.1, 7.1 Hz, 1H), 4.83 (s,2H), 3.15 (t, J=7.4 Hz, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.36 (t, J=7.0 Hz,2H), 2.12-2.01 (m, 2H), 1.79-1.68 (m, 2H), 1.45-1.37 (m, 4H), 0.93 (t,J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.95, 147.16, 135.47,131.33, 128.61, 125.08, 123.79, 123.28, 122.75, 119.71, 31.84, 31.77,31.02, 27.95, 26.64, 22.66, 16.84, 14.21. MS (ESI-TOF) forC₁₈H₂₃N₃[M+H]+ calculated 282.1965, found 282.1904.

5-(2-Amino-3-pentylquinolin-5-yl)pentanenitrile (30b). Compound 16 and4-cyanobutylzinc bromide were used as reagents. Off-white solid (45 mg,76%). ¹H NMR (500 MHz, CDCl₃) δ 7.84 (s, 1H), 7.54 (d, J=8.4 Hz, 1H),7.43 (dd, J=7.1, 8.4 Hz, 11H), 7.07 (dd, J=1.1, 7.1 Hz, 11H), 4.80 (s,2H), 3.02 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 2.37 (t, J=7.1 Hz,2H), 1.93-1.83 (m, 2H), 1.80-1.69 (m, 4H), 1.47-1.36 (m, 4H), 0.93 (t,J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.86, 147.12, 136.99,131.59, 128.56, 124.66, 123.49, 123.01, 122.83, 119.68, 31.82, 31.77,31.69, 29.93, 27.97, 25.25, 22.67, 17.27, 14.22. MS (ESI-TOF) forC₁₉H₂₅N₃[M+H]⁺ calculated 296.2121, found 296.2068.

6-(2-Amino-3-pentylquinolin-5-yl)hexanenitrile (30c). Compound 16 and5-cyanopentylzinc bromide were used as reagents. White solid (38 mg,61%). ¹H NMR (500 MHz, CDCl₃) δ 7.84 (s, 1H), 7.53 (d, J=8.4 Hz, 1H),7.42 (dd, J=7.1, 8.4 Hz, 1H), 7.07 (dd, J=1.2, 7.0 Hz, 1H), 4.80 (s,2H), 2.99 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.34 (t, J=7.1 Hz,2H), 1.80-1.64 (m, 6H), 1.62-1.53 (m, 2H), 1.45-1.36 (m, 4H), 0.93 (t,J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.81, 147.02, 137.81,131.78, 128.58, 124.38, 123.33, 122.91, 122.86, 119.84, 32.30, 31.79,31.75, 30.36, 28.78, 27.98, 25.48, 22.68, 17.29, 14.22. MS (ESI-TOF) forC₂₀H₂₇N₃[M+H]⁺ calculated 310.2278, found 310.2323.

4-(2-Amino-3-pentylquinolin-6-yl)butanenitrile (31a). Compound 27 and3-cyanopropylzinc bromide were used as reagents. White solid (35 mg,62%). ¹H NMR (500 MHz, CDCl₃) δ 7.64 (s, 1H), 7.60 (d, J=8.5 Hz, 1H),7.41 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.1, 8.5 Hz, 1H), 4.80 (s, 2H), 2.89(t, J=7.3 Hz, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.33 (t, J=7.1 Hz, 2H),2.13-1.95 (m, 2H), 1.79-1.65 (m, 2H), 1.45-1.36 (m, 4H), 0.93 (t, J=7.1Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.14, 145.35, 135.19, 133.81,129.65, 126.26, 126.06, 124.58, 124.15, 119.73, 34.18, 31.80, 31.31,27.71, 27.02, 22.69, 16.47, 14.19. MS (ESI-TOF) for C₁₈H₂₃N₃[M+H]⁺calculated 282.1965, found 282.1832.

5-(2-Amino-3-pentylquinolin-6-yl)pentanenitrile (31b). Compound 27 and4-cyanobutylzinc bromide were used as reagents. Pale yellow solid (39mg, 66%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 1H), 7.59 (d, J=8.5 Hz,1H), 7.37 (d, J=1.9 Hz, 1H), 7.34 (dd, J=2.1, 8.5 Hz, 1H), 4.78 (s, 2H),2.76 (t, J=7.4 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H), 2.36 (t, J=7.1 Hz, 2H),1.89-1.80 (m, 2H), 1.76-1.69 (m, 4H), 1.48-1.30 (m, 4H), 0.93 (t, J=7.0Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.97, 145.13, 135.46, 135.22,129.91, 125.82, 125.76, 124.56, 123.98, 119.80, 34.84, 31.80, 31.32,30.41, 27.74, 24.96, 22.70, 17.26, 14.19. MS (ESI-TOF) forC₁₉H₂₅N₃[M+H]⁺ calculated 296.2121, found 296.2146.

6-(2-Amino-3-pentylquinolin-6-yl)hexanenitrile (31c). Compound 27 and5-cyanopentylzinc bromide were used as reagents. Pale yellow solid (40mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 1H), 7.58 (d, J=8.5 Hz,1H), 7.37 (d, J=1.9 Hz, 1H), 7.34 (dd, J=2.1, 8.5 Hz, 1H), 4.77 (s, 2H),2.73 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.7 Hz, 2H), 2.33 (t, J=7.1 Hz, 2H),1.78-1.61 (m, 6H), 1.56-1.46 (m, 2H), 1.44-1.36 (m, 4H), 0.93 (t, J=7.0Hz, 3H). ¹³C NMR (126 MHz, CDCl3) δ 155.89, 145.03, 136.28, 135.24,130.01, 125.75, 125.63, 124.55, 123.88, 119.93, 35.44, 31.81, 31.33,30.77, 28.42, 27.76, 25.47, 22.70, 17.27, 14.19. MS (ESI-TOF) forC₂₀H₂₇N₃ [M+H]⁺ calculated 310.2278, found 310.2309.

4-(2-Amino-3-pentylquinolin-7-yl)butanenitrile (32a). Compound 28 and3-cyanopropylzinc bromide were used as reagents. Pale yellow solid (33mg, 59%). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.55 (d, J=8.1 Hz,1H), 7.45 (s, 1H), 7.09 (dd, J=1.7, 8.1 Hz, 1H), 4.83 (s, 2H), 2.91 (t,J=7.3 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.12-2.02(m, 2H), 1.78-1.68 (m, 2H), 1.51-1.31 (m, 4H), 0.93 (t, J=7.0 Hz, 3H).¹³C NMR (126 MHz, CDCl3) δ 156.54, 146.63, 140.61, 135.31, 127.40,124.69, 123.73, 123.46, 123.24, 119.70, 34.72, 31.80, 31.27, 27.73,26.85, 22.69, 16.52, 14.19. MS (ESI-TOF) for C₁₈H₂₃N₃[M+H]⁺ calculated282.1965, found 282.1978.

5-(2-Amino-3-pentylquinolin-7-yl)pentanenitrile (32b). Compound 28 and4-cyanobutylzinc bromide were used as reagents. Off-white solid (36 mg,61%). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.54 (d, J=8.1 Hz, 1H),7.43 (s, 1H), 7.09 (dd, J=1.7, 8.2 Hz, 1H), 4.81 (s, 2H), 2.79 (t, J=7.4Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.1 Hz, 2H), 1.94-1.81 (m,2H), 1.77-1.63 (m, 4H), 1.45-1.36 (m, 4H), 0.93 (t, 3H). ¹³C NMR (126MHz, CDCl₃) δ 156.44, 146.56, 142.18, 135.36, 127.15, 124.52, 123.82,123.20, 123.00, 119.77, 35.26, 31.80, 31.26, 30.06, 27.75, 24.87, 22.69,17.22, 14.19. MS (ESI-TOF) for C₁₉H₂₅N₃[M+H]⁺ calculated 296.2121, found296.2168.

6-(2-Amino-3-pentylquinolin-7-yl)hexanenitrile (32c). Compound 28 and5-cyanopentylzinc bromide were used as reagents. Pale yellow solid (39mg, 63%). MS (ESI-TOF) for C₂₀H₂₇N₃[M+H]⁺ calculated 310.2278, found310.2309.

4-(2-Amino-3-pentylquinolin-8-yl)butanenitrile (33). Compound 29 and3-cyanopropylzinc bromide were used as reagents. Pale yellow solid (30mg, 53%). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.49 (dd, J=1.5, 8.0Hz, 1H), 7.35 (dd, J=1.4, 7.1 Hz, 1H), 7.16 (dd, J=7.1, 8.0 Hz, 1H),4.79 (s, 2H), 3.23 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.32 (t,J=7.1 Hz, 2H), 2.19-2.09 (m, 2H), 1.79-1.66 (m, 2H), 1.45-1.33 (m, 4H),0.93 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.58, 145.03,135.76, 135.33, 128.76, 125.91, 124.72, 123.64, 122.30, 120.54, 31.83,31.28, 30.49, 27.78, 26.53, 22.70, 16.95, 14.19. MS (ESI-TOF) forC₁₈H₂₃N₃[M+H]⁺ calculated 282.1965, found 282.2008.

Compounds 34a-c were synthesized similarly as compound 18a.

5-(4-Aminobutyl)-3-pentylquinolin-2-amine (34a). Compound 30a was usedas reagent. White solid (20 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 7.95 (s,1H), 7.42-7.35 (m, 2H), 7.08 (dd, J=3.1, 5.1 Hz, 1H), 3.00 (t, J=7.6 Hz,2H), 2.69-2.63 (m, 4H), 1.78-1.64 (m, 4H), 1.61-1.50 (m, 2H), 1.46-1.40(m, 4H), 0.95 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 157.97,147.47, 139.74, 133.37, 129.56, 125.18, 123.77, 123.64, 123.41, 42.51,33.75, 33.21, 32.72, 32.07, 29.82, 29.05, 23.68, 14.47. MS (ESI-TOF) forC₁₈H₂₇N₃[M+H]⁺ calculated 286.2278, found 286.2218.

5-(5-Aminopentyl)-3-pentylquinolin-2-amine (34b). Compound 30b was usedas reagent. White solid (21 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 7.94 (s,1H), 7.42-7.32 (m, 2H), 7.06 (dd, J=2.9, 5.4 Hz, 1H), 2.98 (t, J=7.6 Hz,2H), 2.67 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H), 1.78-1.65 (m, 4H),1.57-1.47 (m, 2H), 1.49-1.39 (m, 6H), 0.95 (t, J=7.0 Hz, 3H). ¹³C NMR(126 MHz, MeOD) δ 157.96, 147.46, 139.91, 133.37, 129.57, 125.12,123.73, 123.58, 123.39, 42.53, 33.77, 33.35, 32.69, 32.39, 32.04, 29.03,27.94, 23.68, 14.47. MS (ESI-TOF) for C₁₉H₂₉N₃[M+H]⁺ calculated300.2434, found 300.2374.

5-(6-Aminohexyl)-3-pentylquinolin-2-amine (34c). Compound 30c was usedas reagent. White solid (18 mg, 57%). ¹H NMR (500 MHz, MeOD) δ 7.95 (s,1H), 7.41-7.32 (m, 2H), 7.06 (dd, J=3.0, 5.3 Hz, 1H), 2.98 (t, J=7.6 Hz,2H), 2.67 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 1.71 (dq, J=7.8,15.5 Hz, 4H), 1.50-1.37 (m, 10H), 0.95 (t, J=7.0 Hz, 3H). ¹³C NMR (126MHz, MeOD) δ 157.96, 147.45, 140.00, 133.37, 129.56, 125.08, 123.72,123.55, 123.39, 42.40, 33.46, 33.34, 32.68, 32.51, 32.00, 30.48, 28.99,27.93, 23.68, 14.47. MS (ESI-TOF) for C₂₀H₃₁N₃[M+H]⁺ calculated314.2591, found 314.2537.

Compound 34d was synthesized similarly as compound 18d.

4-(2-Amino-3-pentylquinolin-5-yl)butanamide (34d). Compound 30a was usedas reagent. White solid (15 mg, 50%). ¹H NMR (500 MHz, MeOD) δ 8.02 (s,1H), 7.45-7.31 (m, 2H), 7.08 (dd, J=2.9, 5.4 Hz, 1H), 3.01 (t, J=7.7 Hz,2H), 2.68 (t, J=7.7 Hz, 2H), 2.30 (t, J=7.3 Hz, 2H), 2.03-1.91 (m, 2H),1.80-1.66 (m, 2H), 1.48-1.38 (m, 4H), 0.94 (t, J=7.0 Hz, 3H). ¹³C NMR(126 MHz, MeOD) δ 178.76, 157.96, 147.27, 139.18, 133.57, 129.64,125.45, 123.92, 123.69, 123.43, 35.95, 32.85, 32.76, 32.13, 29.12,28.38, 23.68, 14.47. MS (ESI-TOF) for C₁₈H₂₅N30 [M+H]⁺ calculated300.2070, found 300.2025.

1-(4-(2-Amino-3-pentylquinolin-5-yl)butyl)guanidine (34e).1H-Pyrazole-1-carboxamidine hydrochloride (16 mg, 0.11 mmol) and Et₃N(15.3 μL, 0.11 mmol) were added to a solution of compound 34a (28.5 mg,0.1 mmol) in MeOH (2 mL), and the reaction mixture was stirred for 3 hat room temperature. The solvent was removed under reduced pressure andthe crude material was purified by basic-alumina column chromatography(30% MeOH/CH₂Cl₂) to obtain 34e as a white solid (16 mg, 49%). ¹H NMR(500 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.60 (t, J=5.7 Hz, 1H), 7.36-7.24 (m,3H), 6.98 (dd, J=3.1, 5.3 Hz, 1H), 6.84 (s, 2H), 6.22 (s, 2H), 3.13 (q,J=6.9 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.68-1.56(m, 4H), 1.58-1.46 (m, 2H), 1.39-1.29 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).¹³C NMR (126 MHz, DMSO-d₆) δ 156.72, 156.66, 146.95, 137.62, 130.71,127.62, 123.66, 123.27, 121.56, 121.26, 40.52, 31.08, 30.96, 30.56,28.36, 27.64, 27.62, 22.03, 14.00. MS (ESI-TOF) for C₁₉H₂₉N₅[M+H]⁺calculated 328.2496, found 328.2444.

Compounds 35a-c, 36a-c and 37 were synthesized similarly as compound18a.

6-(4-Aminobutyl)-3-pentylquinolin-2-amine (35a). Compound 31a was usedas reagent. White solid (16 mg, 56%). ¹H NMR (500 MHz, MeOD) δ 7.70 (s,1H), 7.48-7.40 (m, 211), 7.36 (dd, J=2.0, 8.5 Hz, 11H), 2.73 (t, J=7.5Hz, 2H), 2.66 (t, J=7.3 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 1.76-1.66 (m,4H), 1.57-1.47 (m, 2H), 1.46-1.39 (m, 4H), 0.94 (t, J=7.1 Hz, 3H). ¹³CNMR (126 MHz, MeOD) δ 158.06, 145.47, 137.66, 136.72, 131.08, 126.94,125.75, 125.30, 124.97, 42.38, 36.34, 33.20, 32.78, 31.81, 29.96, 28.96,23.68, 14.43. MS (ESI-TOF) for C₁₈H27N₃ [M+H]⁺ calculated 286.2278,found 286.2283.

6-(5-Aminopentyl)-3-pentylquinolin-2-amine (35b). Compound 31b was usedas reagent. Off-white solid (19 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 7.70(s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.41 (s, 11H), 7.35 (dd, J=2.0, 8.5 Hz,11H), 2.72 (t, J=7.6 Hz, 2H), 2.66-2.58 (m, 4H), 1.76-1.65 (m, 4H),1.55-1.48 (m, 2H), 1.47-1.35 (m, 6H), 0.95 (t, J=6.9 Hz, 3H). ¹³C NMR(126 MHz, MeOD) δ 158.03, 145.42, 137.86, 136.72, 131.09, 126.88,125.73, 125.30, 124.92, 42.50, 36.48, 33.66, 32.80, 32.61, 31.82, 28.97,27.61, 23.68, 14.43. MS (ESI-TOF) for C₁₉H₂₉N₃[M+H]⁺ calculated300.2434, found 300.2487.

6-(6-Aminohexyl)-3-pentylquinolin-2-amine (35c). Compound 31c was usedas reagent. Off-white solid (20 mg, 64%). ¹H NMR (500 MHz, MeOD) δ 7.70(s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J=2.0, 8.5 Hz,1H), 2.70 (t, J=7.6 Hz, 2H), 2.65-2.57 (m, 4H), 1.76-1.62 (m, 4H),1.49-1.33 (m, 10H), 0.94 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ158.02, 145.41, 137.96, 136.71, 131.10, 126.86, 125.72, 125.30, 124.90,42.52, 36.50, 33.73, 32.80, 32.70, 31.83, 30.18, 28.97, 27.89, 23.68,14.44. MS (ESI-TOF) for C₂₀H₃₁N₃[M+H]⁺ calculated 314.2591, found314.2649.

7-(4-Aminobutyl)-3-pentylquinolin-2-amine (36a). Compound 32a was usedas reagent. Off-white solid (19 mg, 67%). ¹H NMR (500 MHz, MeOD) δ 7.71(s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.33 (s, 1H), 7.10 (dd, J=1.7, 8.2 Hz,1H), 2.75 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz,2H), 1.78-1.65 (m, 4H), 1.58-1.48 (m, 2H), 1.46-1.39 (m, 4H), 0.94 (t,J=7.0 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 158.52, 147.11, 144.79, 136.77,128.05, 124.90, 124.62, 123.96, 123.62, 42.44, 36.97, 33.45, 32.77,31.75, 29.78, 28.97, 23.68, 14.42. MS (ESI-TOF) for C₁₈H₂₇N₃[M+H]⁺calculated 286.2278, found 286.2287.

7-(5-Aminopentyl)-3-pentylquinolin-2-amine (36b). Compound 32b was usedas reagent. White solid (18 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 7.71 (s,1H), 7.53 (d, J=8.1 Hz, J H), 7.32 (s, 1H), 7.08 (dd, J=1.7, 8.1 Hz,1H), 2.74 (t, J=7.6 Hz, 2H), 2.65-2.58 (m, 4H), 1.76-1.66 (m, 4H),1.56-1.47 (m, 2H), 1.46-1.36 (m, 6H), 0.94 (t, J=7.0 Hz, 3H). 13C NMR(126 MHz, MeOD) δ 158.52, 147.10, 144.96, 136.78, 128.02, 124.88,124.64, 123.90, 123.58, 42.47, 37.08, 33.62, 32.78, 32.38, 31.75, 28.97,27.62, 23.68, 14.43. MS (ESI-TOF) for C₁₉H₂₉N₃[M+H]⁺ calculated300.2434, found 300.2486.

7-(6-Aminohexyl)-3-pentylquinolin-2-amine (36c). Compound 32c was usedas reagent. White solid (20 mg, 64%). ¹H NMR (500 MHz, MeOD) δ 7.71 (d,J=0.9 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.08 (dd, J=1.7,8.1 Hz, 1H), 2.73 (t, J=7.6 Hz, 2H), 2.66-2.56 (m, 4H), 1.78-1.65 (m,4H), 1.55-1.35 (m, 10H), 0.94 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, MeOD)δ 158.50, 147.09, 145.03, 136.78, 128.00, 124.86, 124.65, 123.89,123.56, 42.40, 37.07, 33.42, 32.79, 32.43, 31.75, 30.14, 28.98, 27.85,23.69, 14.43. MS (ESI-TOF) for C₂₀H₃₁N₃[M+H]⁺ calculated 314.2591, found314.2646.

8-(4-Aminobutyl)-3-pentylquinolin-2-amine (37). Compound 33 was used asreagent. White solid (17 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 7.68 (s,1H), 7.44 (dd, J=1.5, 8.0 Hz, 1H), 7.32 (dd, J=1.4, 7.1 Hz, 1H), 7.10(dd, J=7.1, 8.0 Hz, 1H), 3.06 (t, J=7.7 Hz, 2H), 2.69 (t, J=7.1 Hz, 2H),2.62 (t, J=7.7 Hz, 2H), 1.81-1.68 (m, 4H), 1.61-1.51 (m, 2H), 1.46-1.39(m, 4H), 0.94 (t, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 157.96,145.92, 137.83, 137.02, 129.40, 126.33, 125.61, 125.14, 122.79, 42.40,33.63, 32.83, 32.10, 31.86, 28.96, 28.93, 23.69, 14.43. MS (ESI-TOF) forC₁₈H₂₇N₃ [M+H]⁺ calculated 286.2278, found 286.2283.

2-Amino-4,6-dibromobenzaldehyde (40). A solution of compound 38 (737 mg,2.5 mmol) in THF (20 mL) was added slowly to a solution of LiAlH₄ (10mL, 10 mmol, 1.0 M in THF) in THE (10 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred for 4 h at 25° C. Thereaction mixture was carefully quenched with ice-cold water (1 mL) at 0°C. and 10% NaOH (1 mL) was added. The resulting mixture was stirred for10 min at room temperature, filtered through celite and washed withCH₂Cl₂ (50 mL). The resulting filtrate was dried over Na₂SO₄ andconcentrated under reduced pressure and the crude material was purifiedby flash column chromatography (30% EtOAc/hexanes) to obtain thecompound 39 as an off-white solid (386 mg, 55%). MS (ESI-TOF) forC₇H₇Br₂NO [M+H]⁺ calculated 279.8967, found 279.8975. To a solution ofcompound 39 (351 mg, 1.25 mmol) in CH₂Cl₂ (10 mL) was added MnO₂ (326mg, 3.75 mmol, activated). The mixture was stirred for 6 h and thenfiltered over celite. The mixture was concentrated and purified by flashchromatography (20% EtOAc/hexanes) to give compound 40 as a yellow solid(286 mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H), 7.07 (d, J=1.8Hz, 1H), 6.81 (d, J=1.1 Hz, 1H), 6.56 (s, 2H). ¹³C NMR (126 MHz, CDCl₃)δ 194.69, 152.20, 130.08, 129.98, 124.03, 118.97, 113.96. MS (ESI-TOF)for C₇H5 Br₂NO [M+H]⁺ calculated 277.8811, found 277.8811.

Compound 41 was synthesized similarly as compound 16.

5,7-Dibromo-3-pentylquinolin-2-amine (41). Compound 40 was used asreagent. Off-white solid (242 mg, 65%). ¹H NMR (400 MHz, CDCl₃) δ 7.96(s, 1H), 7.77 (dd, J=0.8, 1.9 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 4.98 (s,2H), 2.58 (t, J=7.6 Hz, 2H), 1.81-1.68 (m, 2H), 1.48-1.36 (m, 4H), 0.94(t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 157.24, 147.77, 134.54,128.98, 128.00, 125.45, 122.50, 121.99, 121.86, 31.78, 31.35, 27.55,22.65, 14.18. MS (ESI-TOF) for C₁₄H₁₆Br₂N₂[M+H]³⁰ calculated 370.9753,found 370.9747.

5,5′-(2-amino-3-pentylquinoline-5,7-diyl)bis(pentan-1-amine) (43). To asolution of compound 41 (74 mg, 0.2 mmol) in THF (2 mL) were added4-cyanobutylzinc bromide (1.6 mL, 0.8 mmol, 0.5 M in THF) and Pd(PPh₃)₄(23 mg, 0.02 mmol). The resulting reaction mixture was stirred at 65° C.under nitrogen atmosphere for 24 h. The reaction mixture was dilutedwith water and extracted with EtOAc (3×10 mL). The combined organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (20% MeOH/CH₂Cl₂) toobtain the compound 42 as a pale yellow solid (19 mg, 25%). MS (ESI-TOF)for C₂₄H₃₂N₄[M+H]⁺ calculated 377.2700, found 377.2691. A solution ofcompound 42 (19 mg, 0.05 mmol) in THF (5 mL) was added slowly to asolution of LiAlH₄ (0.5 mL, 0.5 mmol, 1.0 M in THF) in THF (3 mL) at 0°C. under nitrogen atmosphere. The reaction mixture was stirred for 2 hat 25° C. and 2 h at 60° C. The reaction mixture was carefully quenchedwith ice-cold water (1 mL) at 0° C. and 10% NaOH (1 mL) was added. Theresulting mixture was stirred for 10 min at room temperature, filteredthrough celite and washed with CH₂Cl₂ (25 mL). The resulting filtratewas dried over Na₂SO₄ and concentrated under reduced pressure and thecrude material was purified by semi-preparative reverse phase HPLC toobtain the compound 43 as a white solid (5 mg, 26%). ¹H NMR (400 MHz,MeOD) δ 8.33 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 3.07 (t, J=7.7 Hz,2H), 2.94 (t, J=7.6 Hz, 4H), 2.86-2.73 (m, 4H), 1.82-1.66 (m, 10H),1.58-1.40 (m, 8H), 0.95 (t, J=6.8 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ154.80, 148.71, 141.75, 138.97, 136.98, 128.10, 125.79, 119.63, 115.24,40.68, 40.68, 36.73, 32.74, 32.45, 32.12, 31.61, 30.84, 29.02, 28.52,28.42, 27.37, 27.14, 23.63, 14.44. MS (ESI-TOF) for C₂₄H₄₀N₄[M+H]⁺calculated 385.3326, found 385.3330.

Protein expression, purification and crystallization. The extracellulardomain of human TLR8 (hTLR8, residues 27-827) was prepared as describedpreviously (Tanji, H. et al. Science. 2013, 339, 1426-1429), and wasconcentrated to 16 mg/mL in 10 mM MES (pH 5.5), 50 mM NaCl. The proteinsolutions for the crystallization of hTLR8/compound complexes containedhTLR8 (8.5 mg/mL) and compound (protein:compound molar ratio of 1:10) ina crystallization buffer containing 7 mM MES (pH 5.5), 35 mM NaCl.Crystallization experiments were performed with sitting-dropvapor-diffusion methods at 293 K. Crystals of hTLR8/compound wereobtained with reservoir solutions containing 9-12% (w/v) PEG3350, 0.3 Mpotassium formate, and 0.1 M sodium citrate (pH 4.8-5.2).

Data collection and structure determination. Diffraction datasets werecollected on beamlines PF-AR NE3A (Ibaraki, Japan) and SPring-8 BL41XUunder cryogenic conditions at 100 K. Crystals of hTLR8/compound weresoaked into a cryoprotectant solution containing 15% (w/v) PEG3350, 0.23M potassium formate, 75 mM sodium citrate pH 4.8-5.2, 7.5 mM MES pH 5.5,38 mM NaCl, and 25% glycerol. Datasets were processed using the HKL2000package (Ostinowski, Z. M. et al. Methods Enzymol. 1997, 276, 307-32) orimosfim (Battye, T. G. et al. Acta Crystallogr. D Biol. Crystallogr.2011, 67, 271-281). HTLR8/compound structures were determined by themolecular replacement method using the Molrep program (Vagin, A. et al.Acta Crystallogr. D Biol. Crystallogr. 2010, 66, 22-25) with thehTLR8/CL097 structure (PDB ID: 3W3J) as a search model. The model wasfurther refined with stepwise cycles of manual model building using theCOOT program (Emsley, P. et al. Acta Crystallogr. D Biol. Crystallogr.2004, 60, 2126-2132) and restrained refinement using REFMAC (Murshudov,G. N. et al. Acta Crystallogr. D Biol. Crystallogr. 1997, 53, 240-255)until the R factor was converged. Compound molecule, N-glycans, andwater molecules were modeled into the electron density maps at thelatter cycles of the refinement. The quality of the final structure wasevaluated with PROCHECK (Laskowski, R. A. M. et al. J. Appl.Crystallogr. 1993, 26, 283-291). The statistics of the data collectionand refinement are also summarized in Table 2. The figures representingstructures were prepared with PyMOL (Schrödinger, New York, N.Y.).Coordinates have been deposited in the Protein Data Bank of the ResearchCollaboratory for Structural Bioinformatics; PDB codes for compounds 1and 2 are, respectively, 5AWD and 5AWB.

Human TLR8-specific Reporter Gene assays (NF-κB induction), andTLR-2/-3/-4/-5/-7/-9- and NOD-1/NOD-2 Counter-screens: The induction ofNF-κB was quantified using human TLR-2/3/-4/-5/-7/-8/-9 andNOD-1/NOD-2-specific, rapid-throughput, liquid handler-assisted reportergene assays as previously described by us (Jenkins, M. K. et al. Annu.Rev. Immunol. 2001, 19, 23-45; Shukla, N. M. et al. J. Med. Chem. 2010,53, 4450-4465; Agnihotri, G. et al. J. Med. Chem. 2011, 54, 1490-1510;Ukani, R. et al. Bioorg. Med. Chem. Lett. 2012, 22, 293-295). HEK293cells stably co-transfected with the appropriate hTLR (or NOD) andsecreted alkaline phosphatase (sAP) were maintained in HEK-BLUE™Selection medium. Stable expression of secreted alkaline phosphatase(sAP) under control of NF-κB/AP-1 promoters is inducible by appropriateTLR/NOD agonists, and extracellular sAP in the supernatant isproportional to NF-κB induction. Reporter cells were incubated at adensity of ˜105 cells/ml in a volume of 80 μl/well, in 384-well,flat-bottomed cell culture-treated microtiter plates in the presence ofgraded concentrations of stimuli. sAP was assayed spectrophotometricallyusing an alkaline phosphatase-specific chromogen (present inHEK-detection medium as supplied by InvivoGen) at 620 nm.

Immunoassays for cytokines. Fresh human peripheral blood mononuclearcells (hPBMC) were isolated from human blood obtained by venipuncturewith informed consent and as per institutional guidelines onFicoll-Hypaque gradients. Aliquots of PBMCs (105 cells in 100 μL/well)were stimulated for 12 h with graded concentrations of test compounds.Supernatants were isolated by centrifugation, and were assayed induplicates using analyte-specific multiplexed cytokine/chemokine beadarray assays as reported by us previously (Beesu, M. et al. J. Med.Chem. 2014, 57, 7325-7341).

Rabbit Immunization and CRM197-specific Immunoassays: All experimentswere performed at Harlan Laboratories (Indianapolis, Ind.) in accordancewith institutional guidelines. All antigen/adjuvant preparations wereentirely aqueous; no liposomal or emulsifying agents were used. Cohortsof adult female New Zealand White rabbits (n=4) were immunizedintramuscularly in the flank region with (a) 10 μg of CRM197 (Malito, E.et al. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 5229-5234) in 0.2 mLsaline (unadjuvanted control), or (b) 10 μg of CRM197 in 0.2 mL salineplus 100 μg of lead TLR8 agonists. Pre-immune test-bleeds were firstobtained via venipuncture of the marginal vein of the ear. Animals wereimmunized on Days 1, 15 and 28. A final test-bleed was performed via themarginal vein of the ear on Day 38. Sera were stored at −80° C. untilused. CRM197-specific ELISAs were performed in 384-well format usingautomated liquid handling methods as described by us elsewhere (Shukla,N. M. et al. PLoS ONE. 2012, 7, e43612). A precision 2000 liquid handler(Bio-Tek, Winooski, Vt.) was used for all serial dilution and reagentaddition steps, and a Bio-Tek ELx405 384-well plate washer was employedfor plate washes; 100 mM phosphate-buffered saline (PBS) pH 7.4,containing 0.1% Tween-20 was used as wash buffer. Nunc-Immuno MaxiSorp(384-well) plates were coated with 30 mL of CRM197 (10 μg/mL) in 100 mMcarbonate buffer, pH 9.0 overnight at 4° C. After 3 washes, the plateswere blocked with 3% bovine serum albumin (in PBS, pH 7.4) for 1 h at r.Serum samples (in quadruplicate) were serially diluted in a separate384-well plate using the liquid handler, and 30 μL of the serumdilutions were transferred using the liquid handler, and the plateincubated at 37° C. for 2 h. The assay plate was washed three times, and30 μl of 1:10,000 diluted appropriate anti-rabbit immunoglobulin (IgG, γchain) conjugated with horseradish peroxidase was added to all wells.Following an incubation step at 37° C. for 1 h, and three washes,tetramethylbenzidine substrate was added at concentrations recommendedby vendor (Sigma). The chromogenic reaction was terminated at 30 min bythe addition of 2M H₂SO₄. Plates were then read at 450 nm using aSpectraMax M4 device (Molecular Devices, Sunnyvale, Calif.).

Eight-color Flow-cytometric immunostimulation experiments: Cell surfacemarker upregulation was determined by flow cytometry using protocols asdescribed previously (Hood, J. D. et al. Hum. Vaccin. 2010, 6, 332-335),and modified for rapid-throughput. Briefly, heparin-anticoagulated wholeblood samples were obtained by venipuncture from healthy humanvolunteers with informed consent and as per guidelines approved by theUniversity of Kansas Human Subjects Experimentation Committee. Serialdilutions of selected compounds were performed using a Bio-Tek Precision2000 XS liquid handler in sterile 96-well polypropylene plates, to whichwere added 100 mL aliquots of anticoagulated whole human blood. Theplates were incubated at 37° C. for 16 h. Negative (endotoxin freewater) controls were included in each experiment. The followingfluorochrome-conjugated antibodies were used: CD3-PE, CD19-FITC,CD56-APC (eBioscience, San Diego, Calif.), CD14-V500, CD28 PE-Cy7, CD40V450, CD80 APC-H7, CD86 PerCP-Cy5.5 (Becton-Dickinson Biosciences, SanJose, Calif.). Following incubation, 2.5 μg of each antibody was addedto wells with a liquid handler, and incubated at 4° C. in the dark for60 min. Following staining, erythrocytes were lysed and leukocytes fixedby mixing 200 mL of the samples in 800 mL pre-warmed Whole BloodLyse/Fix Buffer (Becton-Dickinson Biosciences, San Jose, Calif.) in 96deep-well plates. After washing the cells twice at 300 g for 10 minutesin RPMI, the cells were transferred to a 96-well plate. Flow cytometrywas performed using a BD FACSVerse instrument for acquisition on 100,000gated events. Compensation for spillover was computed for eachexperiment on singly-stained Comp Beads (Becton-Dickinson Biosciences,San Jose, Calif.). CD28, CD40, CD80, and CD86 activation in the majorleukocyte populations, viz., natural killer lymphocytes (NK cells:CD3-CD56+), cytokine-induced killer phenotype (CIK cells: CD3+CD56+), Blymphocytes (CD19+CD3-), T lymphocytes (CD3+CD56-), monocytes (CD14+),polymorphonuclear cells (CD14-) were quantified using FlowJo v 7.0software (Treestar, Ashland, Oreg.).

Results and Discussion

The dual TLR7/8-active regioisomeric imidazoquinolines 1 and 2 (FIG. 1),showed substantially different agonistic potencies in human TLR7 (1:50nM; 2: 215 nM) and TLR8 (1: 55 nM; 2: 14 nM) primary screens (FIGS. 6A,6B). The crystal structures of these two congeners bound to theectodomain of human TLR8 revealed the structural basis of enhancedTLR8-agonistic potency of 2 relative to 1: the 3-aminomethylbenzylsubstituent in 2 forms a strong ionic H-bond (salt bridge) with the sidechain carboxylate of Asp545, while the 4-aminomethylbenzyl substituentin 1 was observed to engage the backbone carbonyl of Gly351 in a weakerH-bond (FIG. 1). The stronger interaction of 2 in its binding site notonly resulted in enhancement of agonistic activity in primary screens(FIGS. 6A, 6B), but also in higher proinflammatory cytokine induction inwhole human blood assays.

The question asked was whether grafting the aminomethylbenzyl group onthe 3-pentyl-quinoline-2-amine structure which was previously reportedto be a pure TLR8 agonist (EC₅₀ of 200 nM) (Kokatla, H. P. et al. Chem.Med. Chem. 2014, 9, 719-723) would result in augmented activity. DirectSNAr displacement of the 4-chloro-3-(pent-1-yn-1-yl)quinolineintermediate 4 (Kokatla, H. P. et al., 2014 supra) with 3- or4-cyanobenzylzinc bromide as nucleophiles (Shiota, T. et al. J. Org.Chem. 1999, 64, 453-457) afforded the 4-substituted 3-pentynylquinolines5a and 5b (Scheme 1); reduction of the nitriles with LiAlH₄ andsubsequent Boc protection of the resultant amines yielded theintermediates 6a and 6b. Installation of the amine at C₂ was performedas reported earlier ((Kokatla, H. P. et al., 2014 supra). Hydrogenationof the alkynyl group and Boc-deprotection furnished the desired targetcompounds 9a and 9b (Scheme 1) which retained specificity for TLR8, butwith marginal improvement in potency (150 nM and 120 nM, respectively;Table 1). In order to examine whether relieving possible steric bulk ofthe aminomethylbenzyl substituent at C4, the synthesis of the4-aminobutyl (14a) and 5-aminopentyl (14b) analogues (Scheme 2) wasundertaken, the lengths of which were found to be optimal in SAR studieson several TLR8-active chemotypes (Yoo, E. et al. J. Med. Chem. 2014,57, 7955-7970; Salunke, D. B. et al. J. Med. Chem. 2012, 55, 8137-8151;Kokatla, H. P. et al. J. Med. Chem. 2013, 56, 6871-6885; Kokatla, H. P.et al. Chem. Med. Chem. 2014, 9, 719-723; Beesu, M. et al. J. Med. Chem.2014, 57, 7325-7341). Installation of the 4-alkyl nitrile groups of10a-b were carried out with cyanoalkylzinc bromides under Negishiconditions (Scheme 2), and the remainder of the sequence of reactionswere similar to those described in Scheme 1. The potencies of 14a and14b remained virtually unchanged (190 nM and 250 nM, respectively; Table1).

The first attempts at attaching amine-bearing appendages on thequinoline core at C4 to allow for additional salt-bridge interactionswith Asp545 appeared unfruitful, however, a systematic examination ofsubstitutions at all other positions was carried out. The goal was toestablish an efficient synthetic strategy to access 5-, 6-, 7- and8-substituted 2-amino-3-pentylquinolines. A one-pot method for thesyntheses of 2-aminoquinoline-3-carboxamides has been reported using2-aminobenzaldehyde and active methylene group-bearing cyanoacetamides(Wang, K. et al. ACS Comb. Sci. 2012, 14, 316-322). ENREF_68 It wasenvisioned that a modified Friedlander synthesis of keybromo-substituted 2-amino-3-pentylquinolines could be directly obtainedvia condensation-cyclization reactions of 2-aminobromobenzaldehydes withheptanenitrile. The initial attempts at model reactions with alkanenitriles and the unsubstituted 2-aminobenzaldehyde proceeded very wellin the presence of n-butyllithium. However, in order to preempt possibledebromination, alternatives were sought and successfully utilizedpotassium tert-butoxide to generate the pivotal bromo-substituted2-amino-3-pentylquinolines (Schemes 3-7).

2-amino-3-pentylquinolines substituted at C5 was targeted with3-aminomethylbenzyl (18a), 4-aminomethylbenzyl (18b), and2-aminomethylbenzyl (18c) substituents, which were obtained by Negishicoupling of corresponding cyanobenzylzinc bromides with 16 (Scheme 3).Substantially improved potencies were observed for both 18a and 18b(EC₅₀: 49 nM and 38 nM, respectively; FIG. 2, Table 1), whereas the2-aminomethylbenzyl-substituted 18c was significantly weaker (EC₅₀: 1000nM; Table 1) than the parent compound, 3, providing evidence that theplacement of the amine on the benzyl substituent was an importantdeterminant of activity. In order to formally test whether the amine wasparticipating in the predicted salt bridge, the nitrile 17a washydrolyzed to the carboxamide analogue 18d (Scheme 3). Compound 18d, aswell as the 5-benzyl analogue 17d were found to be inactive (Table 1),lending support to our hypothesis.

The role of conformational flexibility of the aminomethylbenzylsubstituent at C5 was explored, Accordingly, the aryl-aryl coupled5-(aminomethyl)phenyl analogues 20a and 20b were synthesized via Suzukireaction of cyanophenylboronic acids with 16 (Scheme 4). Compound 20awas entirely inactive and the activity of 20b was attenuated (699 nM),strongly pointing to the indispensability of conformational freedom.These findings prompted the synthesis of 5-aminoalkyl analogues (Schemes5 and 6). The aminobutyl (34a), aminopentyl (34b), and aminohexyl (34c)derivatives could be accessed via Negishi couplings (Scheme 6); thereactivity of 2-cyanoethylzinc bromide with 16, however, was very pooreven under microwave conditions, and the aminopropyl analogue 23 wasaccessed via Heck reaction of acrylonitrile with 16 (Scheme 5). A cleardependence on the length of the alkylamino substituent was observed inthese homologues with progressive increases in potency from theaminopropyl (23: 91 nM), aminobutyl (34a: 27 nM; FIG. 2) and aminopentyl(34b: 9 nM; FIG. 2) analogues; a further in length (34c, aminohexyl) ledto decreased activity (56 nM; Table 1). Conversion of the nitrileprecursor 30a to the carboxamide derivative 34d (Scheme 6) resulted in adramatic decrease in potency (2181 nM; Table 1), once again highlightingthe importance of the presence of a free amino functional group.

The dramatic enhancement of potency in 34b seemed to unambiguouslysupport the hypothesis of a salt-bridge between Asp545 and the5-aminopentyl group of the lead compound. Given thatguanidine-carboxylate interaction in proteins are consequential (Kumar,S. et al. Chembiochem. 2002, 3, 604-617; Singh, J. et al. FEBS Lett.1987, 224, 161-171), and significant gains in interaction energies areobserved in drugs such as zanamivir and peramivir whose crystalstructures show strong salt-bridges between their guanidinium functionalgroups and the Asp/Glu residues that they interact with (Kerry, P. S. etal. Sci. Rep. 2013, 3, 2871), the guanidine derivative 34e wassynthesized from 34a (Scheme 6), the length of the C5 substituent ofwhich was calculated to be comparable to that of 34b. Surprisingly, aprecipitous fall in activity (2862 nM; Table 1) was found, the reasonsfor which are yet to be understood.

Aminoalkyl substitutions at C6 (35a-35c), C7 (36a-36c), and C8 (37)(Scheme 6) were investigated. Compounds 35a-35c showed slight decreasesin activity while analogues 36a-36c displayed modest gains in potency,with the most active compound being the7-(5-aminopentyl)-3-pentylquinolin-2-amine, 36b (50 nM). TheC8-substituted analogue 37 was entirely devoid of activity (Table 1).Noting that the most potent analogues possessed an aminopentylsubstituent either at C5 (34b, 9 nM) or C7 (36b, 50 nM), adually-substituted analogue was synthesized. The key precursor,2-amino-4,6-dibromobenzaldehyde was synthesized from2-amino-4,6-dibromobenzoic acid using conventional methods, andalkylamino substituents at C5 and C7 installed via Negishi reaction of41 with 4-cyanobutylzinc bromide (Scheme 7). The disubstituted analogue43, however, was found to be weaker (621 nM) than the parent compound.

The most potent analogue 34b was characterized further incytokine/chemokine induction profiles in a panel of secondary screensemploying human peripheral blood mononuclear cells as well as wholehuman blood. Consistent with its specificity and potency for TLR8, notonly was the induction of a specific set of proinflammatory cytokineswas observed, including TNF-α, IL-12 and IFN-γ (FIG. 3), but also thatthe potency of 34b was significantly higher than that of both 3(TLR8-specific) and 1 (dual TLR7/8-active).

The adjuvantic activity of 34b (TLR8 EC50: 9 nM) was compared with thatof 3 (200 nM), as well as a first-generation C2-butylfuro[2,3-c]quinoline (1600 nM) (Kokatla, H. P. et al. J. Med. Chem.2013, 56, 6871-6885) in a rabbit model of immunization, using theDiphtheria toxin mutein CRM197 as a model antigen (Malito, E. et al.Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 5229-5234). A clear dependencebetween antigen-specific IgG titers and TLR8-agonistic potency wasobserved (FIG. 4).

One aspect of the inventors' work on vaccine adjuvant discovery, inaddition to elucidating of structure-activity relationships in leadcandidate vaccine adjuvants, is to delineate specific mechanisms bywhich these compounds elicit adjuvantic effects. As alluded to earlier,the understanding of how efferent signals arising from activation of theinnate immune system engage particular pathways in downstream adaptiveimmune responses culminating, for instance, in the generation ofantigen-specific humoral responses is nascent and fragmentary. One ofthe questions addressed is how various chemotypes acting on differentinnate immune receptors with divergent outcomes effect enhancement ofimmune responses. Pure TLR8 agonists, as discussed earlier, evoke theproduction of Th1-biased cytokines such as TNF-α, IL-1, IL-12, IL-18 andIFN-γ from cells of the monocytoid lineage; pure TLR7-active compoundsinduce the copious production of IFN-α from low-abundance plasmacytoidcells, activate natural killer (NK) (Hood, J. D. et al. Hum. Vaccin.2010, 6, 332-335) and induce mitogenicity in B lymphocytes, and are muchweaker in inducing TNF-α and IFN-γ; TLR2 agonists, in contrast, activateneutrophils as evidenced by rapid upregulation of CD11b and p38 MAPkinase activity (Salunke, D. B. et al. J. Med. Chem. 2012, 55,3353-3363; Salunke, D. B. et al. J. Med. Chem. 2013, 56, 5885-5900). Theobservation that all these chemotypes display adjuvantic activities maysignify that the disparate outcomes in different cell types may point todifferent mechanisms mediating adjuvantic activities such as, asdiscussed earlier, enhanced antigen uptake and presentation by APCs (Xu,W. et al. Front. Immunol. 2014, 4, 504; Platt, A. M. et al. Adv.Immunol. 2013, 120, 51-68; Teijeira, A. et al. Front. Immunol. 2013, 4,433; Teijeira, A. et al. Semin. Immunopathol. 2014, 36, 261-274),enhanced CD4+ T cell help (Jenkins, M. K. et al. Annu. Rev. Immunol.2001, 19, 23-45; Garside, P. et al. Science 1998, 281, 96-99; Miga, A.J. et al. Eur. J. Immunol. 2001, 31, 959-965), or affinity maturation ofantibodies (McHeyzer-Williams, L. J. et al. Curr. Opin. Immunol. 2009,21, 266-273; Nurieva, R. I. et al. Cell. Molec. Immunol. 2010, 7,190-197).

In an attempt to understand how TLR8 agonism may modulate adaptiveimmune functions, eight-color flow cytometry was used to interrogateactivation markers (CD40, CD80) in major cellular subsets (granulocytes,monocytes (CD14⁺), T cells (CD3⁺), B cells (CD19⁺), NK cells (CD3⁻CD56⁺)and cytokine-induced killer cells (CD3⁺CD56⁺) in human whole bloodstimulated with 34b, the significantly weaker TLR8-specific 3, as wellas the potent, dual TLR7/8-active 1; it was found that whereas both 34band 1 upregulate CD40, specifically in CD14⁺ monocytes (and not in othersubsets), the TLR8 stimulation with 34b strongly induces CD80 expressionin the monocytes (FIG. 5) and, in these assays, differences in potencybetween 34b and 1 become readily evident (FIG. 5). These results hint ata possible specific role of TLR8 agonists at enhancing antigenpresentation, and point a way forward to exploring this phenomenon ingreater detail.

In conclusion, this approach of augmenting potency by exploiting keyinteractions identified in crystallographic studies of TLR8 has yieldednovel analogues of extraordinary potency and specificity which areproving useful in understanding the immunological basis of adjuvanticityin this chemotype.

TABLE 1 EC₅₀ values of compounds in human TLR 8-specific reporter geneassays TLR8 Agonistic S. Activity No. Structure (nM)  9a

150  9b

120 14a

190 14b

250 18a

49 18b

38 18c

1000 17d

Inactive 18d

Inactive 20a

Inactive 20b

699 23 

91 34a

27 34b

9 34c

56 34d

2181 34e

2862 35a

727 35b

519 35c

1016 36a

60 36b

50 36c

85 37 

Inactive 43 

621

TABLE 2 Data collection and refinement statistics for TLR8/1, and TLR8/2TLR8/1 TLR8/2 Data Collection X-ray source PF-NE3A PF-NE3A Wavelength1.0000 1.0000 Space group C2 C2 Unit cell parameters a (Å) 135.7 134.9 b(Å) 106.7 107.1 c (Å) 72.2 72.1 β (°) 106.2 106.3 Resolution (Å) 2.052.10 Completeness (%) 99.8 (99.9) 98.9 (99.6) Redundancy 3.5 (3.4) 3.1(2.8) R_(sym) (l)^(b) 0.077 (0.424) 0.073 (0.759) Average l/σ(l) 9.6(2.6) 26.4 (2.0) Refinement Resolution range (Å) 69.28-2.05 27.50-2.10No. of reflections used 58,440 53,673 Model 1 × TLR8 1 × TLR8 AverageB-factor (Å²) 38.4 50.1 R (%)^(c) 21.5 20.1 R_(free) (%)^(d) 26.9 25.9Rms deviations Bond length (Å) 0.011 0.016 Bond angles (°) 1.61 1.89^(a)Highest resolution shell is shown in parentheses. ^(b)R_(sym) (I) =Σ|I − <I>|/ΣI, where I is the diffraction intensity. ^(c)R = Σ|F_(o) −F_(c)|/ΣF_(o), where F_(o) and F_(c) are the observed and calculatedstructure amplitudes, respectively. ^(d)R_(free) is an R value for a 5%subset of all reflections, but was not used in the refinement.

EMBODIMENTS

The following are non-limiting embodiments of the present disclosure:1. A compound represented by Formula (II):

or a salt thereof, wherein:

R¹, R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of: H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R″, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl,optionally substituted C₂₋₂₀ alkynyl, optionally substituted C₃₋₂₀carbocycle, and optionally substituted 3- to 20-membered heterocycle,wherein at least one of R¹ and R³ is selected from the group consistingof —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl,optionally substituted C₃₋₂₀ carbocycle, and optionally substituted 3-to 20-membered heterocycle;

R⁶ is selected from the group consisting of —OR¹¹, —N(R¹¹)₂, —SR¹¹,optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, and optionally substituted C₂₋₂₀ alkynyl;

R⁷ and R⁸ are independently selected from H, optionally substitutedC₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, optionallysubstituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle andoptionally substituted 3- to 12-membered heterocycle;

R¹⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted C₃₋₁₂ carbocycle and optionally substituted 3- to12-membered heterocycle; and

R¹¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

2. The compound or salt of embodiment 1, wherein at least one of R¹ andR³ is selected from the group consisting of —OR¹⁰, —N(R¹⁰)₂, —OC(O)R′″,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, optionallysubstituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl, andoptionally substituted C₂₋₂₀ alkynyl.3. The compound or salt of embodiment 2, wherein at least one of R¹ andR³ is selected from the group consisting of optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionally substitutedC₂₋₂₀ alkynyl.4. The compound or salt of embodiment 3, wherein R¹ is optionallysubstituted C₁₋₁₀ alkyl.5. The compound or salt of embodiment 4, wherein R¹ is optionallysubstituted C₁₋₅ alkyl.6. The compound of any one of embodiments 1 to 5, wherein R¹ is selectedfrom the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and the 3- to 12-membered heterocycle are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,—C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂;and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

7. The compound or salt of embodiment 6, wherein R¹ is substituted with—N(R⁵⁰)₂.8. The compound or salt of embodiment 6, wherein R¹ is selected from:

9. The compound or salt of embodiment 3, wherein R³ is optionallysubstituted C₁₋₁₀ alkyl.10. The compound or salt of embodiment 9, wherein R³ is optionallysubstituted C₁₋₅ alkyl.11. The compound of any one of embodiments 1 to 10, wherein R³ isselected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ (alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

12. The compound or salt of embodiment 11, wherein R³ is substitutedwith —N(R⁵⁰)₂.13. The compound or salt of embodiment 11, wherein R³ is selected from:

14. The compound or salt of embodiment 8, wherein R is selected from H,halogen, and —CN.15. The compound or salt of embodiment 14, wherein R³ is hydrogen.16. The compound or salt of embodiment 13, wherein R¹ is selected fromH, halogen, and —CN.17. The compound or salt of embodiment 16, wherein R¹ is hydrogen.18. The compound or salt of any one of embodiments 1 to 17, wherein R²,R⁴, and R⁵ are independently selected from the group consisting of: H,halogen, —OR¹, —N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰, —C(O)R¹⁰,—C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, and optionallysubstituted C₁₋₂₀ alkyl.19. The compound or salt of embodiment 18, wherein R², R⁴, and R⁵ areindependently selected from the group consisting of: H, halogen, —OR¹⁰,—N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, and optionally substituted C₁₋₂₀ alkyl.20. The compound or salt of any one of embodiments 1 to 19, wherein R²,R⁴, and R⁵ are independently selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

21. The compound or salt of any one of embodiments 1 to 20, wherein R²is hydrogen.22. The compound or salt of any one of embodiments 1 to 21, wherein R⁴is hydrogen.23. The compound or salt of any one of embodiments 1 to 22, wherein R⁵is hydrogen.24. The compound or salt of any one of embodiments 1 to 23, wherein R¹⁰is selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

25. The compound or salt of any one of embodiments 1 to 24, wherein R⁶is selected from the group consisting of optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionally substitutedC₂₋₂₀ alkynyl.26. The compound or salt of embodiment 25, wherein R⁶ is selected fromthe group consisting of optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, and optionally substituted C₁₋₁₀ alkynyl.27. The compound or salt of embodiment 26, wherein R⁶ is selected fromthe group consisting of optionally substituted C₁₋₁₀ alkyl.28. The compound or salt of any one of embodiments 1 to 27, wherein R⁶is selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰))₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

29. The compound or salt of embodiment 28, wherein R⁶ is:

30. The compound or salt of any one of embodiments 1 to 29, wherein R⁷and R⁸ are independently selected from H and optionally substitutedC₁₋₁₀ alkyl.31. The compound of any one of embodiments 1 to 30, wherein R⁷ and R⁸are each H.32. The compound or salt of any one of embodiments 1 to 31, wherein R⁷and R⁸ are independently selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, —NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂,—OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂, —S(O)₂R⁵⁰, —S(O)₂OR⁵⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀alkyl-C(O)N(R⁵⁰)₂; and

wherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

33. The compound or salt of any one of embodiments 1 to 32, representedby the Formula:

or a salt of any one thereof.34. The compound or salt of any one of embodiments 1 to 32, representedby the Formula:

or a salt of any one thereof.35. A pharmaceutical composition comprising a compound or salt of anyone of embodiments 1 to 34, and pharmaceutically acceptable excipient.36. The pharmaceutical composition of embodiment 35, wherein thecomposition further comprises a vaccine.37. A method for modulating activity of a human toll-like receptor,comprising administering to a subject in need thereof, a compound offormula (III):

or a salt thereof, wherein:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H, halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰,—C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionallysubstituted C₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀alkynyl, and optionally substituted 3- to 20-membered heterocycle,

wherein at least one of R¹¹, R¹², R¹³, and R¹⁴ is selected from thegroup consisting of —OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂R²⁰ optionally substituted C₃₋₂₀ carbocycle,optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, and optionallysubstituted 3- to 20-membered heterocycle;

R¹⁶ is optionally substituted C₁₋₂₀ alkyl, —OR²¹, —N(R²¹)₂, —SR²¹,optionally substituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀alkynyl;

R¹⁷ and R¹⁸ are independently selected from H, optionally substitutedC₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, optionallysubstituted C₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle andoptionally substituted 3- to 12-membered heterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

38. The method of embodiment 37, wherein modulating the activity of thehuman toll-like receptor comprises agonizing the human toll-likereceptor.39. The method of embodiment 37 or 38, wherein the human toll-likereceptor comprises hTLR8.40. The method of any one of embodiments 37 to 39, wherein the methodfurther comprises administering a vaccine to the subject before, inconjunction with, or after administration of the compound or salt.41. A method of increasing an immune response to an antigen or vaccine,wherein the method comprises administering to a subject in need thereofa compound of Formula (III):

or a salt thereof, wherein:

R¹¹, R², R¹³, R¹⁴, and R¹⁵ are independently selected from the groupconsisting of: H, halogen, —OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰,—C(O)R²⁰, —C(O)OR²⁰, —C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionallysubstituted C₃₋₂₀ carbocycle, optionally substituted C₁₋₂₀ alkyl,optionally substituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀alkynyl, and optionally substituted 3- to 20-membered heterocycle,wherein at least one of R¹¹, R¹², R¹³, and R¹⁴ is selected from thegroup consisting of —OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)NR²⁰, —S(O)₂R²⁰, —S(O)₂OR²⁰, optionally substituted C₃₋₂₀carbocycle, optionally substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, and optionallysubstituted 3- to 20-membered heterocycle;

R¹⁶ is selected from the group consisting of optionally substitutedC₁₋₂₀ alkyl, —OR, —N(R²¹)₂, —SR²¹, optionally substituted C₂₋₂₀ alkenyl,and optionally substituted C₂₋₂₀ alkynyl;

R¹⁷ and R¹⁸ are independently selected from the group consisting of H,optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀ alkynyl, optionally substitutedC₃₋₁₂ carbocycle and optionally substituted 3- to 12-memberedheterocycle;

R²⁰ is independently selected at each occurrence from the groupconsisting of H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted 3- to 12-membered heterocycle and optionallysubstituted C₃₋₁₂ carbocycle; and

R²¹ is independently selected at each occurrence from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl.

42. The method of any one of embodiments 37 to 41, wherein at least oneof R¹¹, R¹², R¹³, and R¹⁴ is selected from the group consisting of—OR²⁰, —NR²⁰ ₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —S(O)₂R²⁰,—S(O)₂OR²⁰ optionally substituted C₁−2° alkyl, optionally substitutedC₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl.43. The method of embodiment 42, wherein at least one of R¹¹, R¹², R¹³,and R¹⁴ is selected from the group consisting of optionally substitutedC₁₋₂₀ alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionallysubstituted C₂₋₂₀ alkynyl.44. The method of embodiment 43, wherein R″ is optionally substitutedC₁₋₁₀ alkyl.45. The method of embodiment 44, wherein R″ is optionally substitutedC₁₋₅ alkyl.46. The method of any one of embodiments 37 to 45, wherein R¹ isselected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

47. The method of embodiment 46, wherein R″ is substituted with—N(R⁶⁰)₂.48. The method of embodiment 46, wherein R″ is selected from:

49. The method of any one of embodiments 44 to 48, wherein R¹³ isoptionally substituted C₁₋₁₀ alkyl.50. The method of embodiment 49, wherein R¹³ is optionally substitutedC₁₋₅ alkyl.51. The method of any one of embodiments 37 to 50, wherein R¹³ isselected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

52. The method of embodiment 51, wherein R¹³ is substituted with—N(R⁶⁰)₂.53. The method of embodiment 51, wherein R¹³ is selected from:

54. The method of any one of embodiments 37 to 48, wherein R¹³ isselected from H, halogen, and —CN.55. The method of embodiment 53, wherein R¹³ is hydrogen.56. The method of any one of embodiments 37 to 43 and 49 to 55, whereinR¹¹ is selected from H, halogen, and —CN.57. The method of embodiment 56, wherein R¹¹ is hydrogen.58. The method of any one of embodiments 37 to 57, wherein R¹², R¹⁴, andR⁵ are independently selected from the group consisting of: H, halogen,—OR²⁰, —N(R²⁰)₂, —SR²⁰, —CN, —NO₂, —OC(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —S(O)₂R²⁰, —S(O)₂OR²⁰, and optionally substituted C₁₋₂₀alkyl.59. The method of embodiment 58, wherein R¹², R¹⁴, and R¹⁵ areindependently selected from the group consisting of: H, halogen, —OR²⁰,—N(R²⁰)₂, —SR²⁰, —CN, —NO₂, and optionally substituted C₁₋₂₀ alkyl.60. The method of any one of embodiments 37 to 58, wherein R¹², R¹⁴, andR¹⁵ are independently selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

61. The method of any one of embodiments 37 to 59, wherein R¹² ishydrogen.62. The method of any one of embodiments 37 to 56, wherein R¹⁴ ishydrogen.63. The method of any one of embodiments 37 to 61, wherein R¹⁵ ishydrogen.64. The method of any one of embodiments 37 to 63, wherein R²⁰ isselected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R″ °, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

65. The method of any one of embodiments 37 to 64, wherein R¹⁶ isselected from the group consisting of optionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀ alkenyl, and optionally substitutedC₂₋₂₀ alkynyl.66. The method of embodiment 65, wherein R¹⁶ is selected from the groupconsisting of optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₁₋₂₀ alkynyl.67. The method of embodiment 66, wherein R¹⁶ is selected from the groupconsisting of optionally substituted C₁₋₁₀ alkyl.68. The method of any one of embodiments embodiment 37 to 67, whereinR¹⁶ is selected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

69. The method of embodiment 68, wherein R¹⁶ is:

70. The method of any one of embodiments 37 to 69, wherein R¹⁷ and R¹⁸are independently selected from H and optionally substituted C₁₋₁₀alkyl.71. The method of embodiment 70, wherein R¹⁷ and R¹⁸ are each H.72. The method of any one of embodiments 37 to 71, wherein R¹⁸ isselected from the group consisting of:

optionally substituted C₁₋₂₀ alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, wherein the C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, —NR⁶⁰C(N(R⁶⁰))N(R⁶⁰)₂,—OC(O)R⁶⁰, —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)N(R⁶⁰)₂, —S(O)₂R⁶⁰, —S(O)₂OR⁶⁰,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, wherein the C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle are optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

optionally substituted C₃₋₂₀ carbocycle and optionally substituted 3- to20-membered heterocycle, wherein the C₃₋₂₀ carbocycle and 3- to20-membered heterocycle optional substituents are one or moresubstituents independently selected from the group consisting of:halogen, —CN, —NO₂, —OR⁶⁰, —SR⁶⁰, —N(R⁶⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, —C₁₋₁₀ alkyl-N(R⁶⁰)₂, —C₁₋₁₀ alkyl-OR⁶⁰, and —C₁₋₁₀alkyl-C(O)N(R⁶⁰)₂; and

wherein R⁶⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.

73. The method of any one of embodiments 37 to 72, wherein the compoundis represented by the Formula:

or a salt of any one thereof.

1.-73. (canceled)
 74. A compound represented by Formula (II):

or a salt thereof, wherein: R³ is selected from the group consisting of—OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, —S(O)₂OR¹⁰, substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, optionallysubstituted C₃₋₂₀ carbocycle, and optionally substituted 3- to20-membered heterocycle; R¹, R², R⁴, and R⁵ are independently selectedfrom the group consisting of H, halogen, —OR¹⁰, —N(R¹⁰)₂, —SR¹⁰, —CN,—NO₂, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰,—S(O)₂OR¹⁰, optionally substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, optionallysubstituted C₃₋₂₀ carbocycle, and optionally substituted 3- to20-membered heterocycle; R⁶ is selected from the group consisting of—OR¹¹, —N(R¹¹)₂, —SR¹¹, optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl; R⁷and R⁸ are each independently H; R¹⁰ is independently selected at eachoccurrence from the group consisting of H, optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀ alkenyl, optionally substitutedC₂₋₁₀ alkynyl, optionally substituted C₃₋₁₂ carbocycle and optionallysubstituted 3- to 12-membered heterocycle; and R¹¹ is independentlyselected at each occurrence from the group consisting of optionallysubstituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, andoptionally substituted C₂₋₁₀ alkynyl.
 75. The compound or salt of claim74, wherein R³ is selected from the group consisting of


76. The compound or salt of claim 74, wherein R³ is selected from thegroup consisting of


77. The compound or salt of claim 74, wherein R¹ is selected from thegroup consisting of


78. The compound or salt of claim 74, wherein R², R⁴, and R⁵ areindependently selected from the group consisting of H, halogen, —OR¹⁰,—N(R¹⁰)₂, —SR¹⁰, —CN, —NO₂, —OC(O)R¹⁰, —C(O)R¹⁰, —C(O)OR¹⁰,—C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —S(O)₂OR¹⁰, and substituted C₁₋₂₀ alkyl. 79.The compound or salt of claim 74, wherein R¹⁰ is selected from the groupconsisting of: optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, whereinthe C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, and C₂₋₂₀ alkynyl optional substituentsare one or more substituents independently selected from the groupconsisting of: halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂,—NR⁵⁰C(N(R⁵⁰))N(R⁵⁰)₂, —OC(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —C(O)N(R⁵⁰)₂,—S(O)₂R⁵⁰, —S(O)₂OR⁵⁰, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, wherein the C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle are optionally substituted with one or more substituentsselected from the group consisting of halogen, —CN, —NO₂, —OR⁵⁰, —SR⁵⁰,—N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀ alkyl —N(R⁵⁰)₂, —C₁₋₁₀alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; and optionally substitutedC₃₋₂₀ carbocycle and optionally substituted 3- to 20-memberedheterocycle, wherein the C₃₋₂₀ carbocycle and 3- to 20-memberedheterocycle optional substituents are one or more substituentsindependently selected from the group consisting of: halogen, —CN, —NO₂,—OR⁵⁰, —SR⁵⁰, —N(R⁵⁰)₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, —C₁₋₁₀alkyl-N(R⁵⁰)₂, —C₁₋₁₀ alkyl-OR⁵⁰, and —C₁₋₁₀ alkyl-C(O)N(R⁵⁰)₂; andwherein R⁵⁰ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, and C₁₋₁₀ haloalkyl.
 80. Thecompound or salt of claim 74, wherein R⁶ is selected from the groupconsisting of optionally substituted C₁₋₂₀ alkyl, optionally substitutedC₂₋₂₀ alkenyl, and optionally substituted C₂₋₂₀ alkynyl.
 81. Thecompound or salt of claim 74, wherein the compound is represented by

or a salt thereof.
 82. A pharmaceutical composition comprising acompound or salt of claim 74, and a pharmaceutically acceptableexcipient, optionally wherein the composition further comprises avaccine.
 83. A method for modulating activity of a human toll-likereceptor, comprising administering to a subject in need thereof acompound of claim 74 or a salt thereof.
 84. The method of claim 83,wherein modulating the activity of the human toll-like receptorcomprises agonizing the human toll-like receptor.
 85. The method ofclaim 83, wherein the human toll-like receptor comprises hTLR8.
 86. Themethod of claim 83, wherein the method further comprises administering avaccine to the subject before, in conjunction with, or afteradministration of the compound or salt thereof.
 87. The method of claim83, wherein R³ is selected from the group consisting of


88. The method of claim 83, wherein R³ is selected from the groupconsisting of


89. The method of claim 83, wherein the compound is represented by

or a salt thereof.
 90. A method of increasing an immune response to anantigen or vaccine, wherein the method comprises administering to asubject in need thereof a compound of claim 74 or a salt thereof. 91.The method of claim 90, wherein the method further comprisesadministering a vaccine to the subject before, in conjunction with, orafter administration of the compound or salt thereof.
 92. The method ofclaim 90, wherein R³ is selected from the group consisting of


93. The method of claim 90, wherein the compound is represented by

or a salt thereof.